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Iniesta-Navalón C, Saorín MR, Neira-Torrecillas JM, Rentero-Redondo L, Garcia-Masegosa I, Gil-Almela J, Urbieta-Sanz E. External Evaluation of Population Pharmacokinetic Models of Ustekinumab in Patients with Inflammatory Bowel Disease. Ther Drug Monit 2025:00007691-990000000-00339. [PMID: 40178486 DOI: 10.1097/ftd.0000000000001329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 02/24/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Population pharmacokinetic (popPK) models are essential tools for optimizing ustekinumab (UST) dosing for the treatment of inflammatory bowel disease (IBD) through therapeutic drug monitoring. The external validation of these models is necessary to ensure their predictive performance and clinical utility. The aim of the study was to externally validate 4 published popPK models of UST in a real-world cohort of patients with IBD using prediction-based and simulation-based diagnostics, as well as Bayesian forecasting. METHODS Four popPK models of UST, identified through a systematic literature review, were evaluated using data from 99 patients with IBD and 374 serum UST concentrations. Predictive performance and Bayesian forecasting were assessed using statistical metrics, including mean prediction error, median prediction error (MDPE), and median absolute prediction error (MADPE). The acceptability criteria (MDPE ±20%, MADPE ≤30%, F20 ≥35%, and F30 ≥50%) were applied. RESULTS None of the models satisfied the predefined acceptability criteria. The Xu et al model demonstrated the best performance, achieving an MDPE of 19.55% and the lowest RMSPE (2.88 mcg/mL), but F20 (20.1%) and F30 (32.4%) values fell below thresholds. The model proposed by Adedokun et al showed strong results in simulation-based diagnostics, with only 5.6% of the observed concentrations outside the prediction interval. CONCLUSIONS The models developed by Xu et al and Adedokun et al exhibited the most promising predictive performance and potential clinical applicability for model-informed precision dosing. Refinements to these models and further research are required to enhance their use in personalized UST therapies for IBD.
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Affiliation(s)
- Carles Iniesta-Navalón
- Department of Hospital Pharmacy, Reina Sofia Hospital of Murcia, Spain
- Department of Pharmacology, School of Medicine, University of Murcia, Spain; and
- Clinical Pharmacokinetics and Applied Pharmacotherapy Group, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Spain
| | - Manuel Ríos Saorín
- Department of Hospital Pharmacy, Reina Sofia Hospital of Murcia, Spain
- Clinical Pharmacokinetics and Applied Pharmacotherapy Group, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Spain
| | | | - Lorena Rentero-Redondo
- Department of Hospital Pharmacy, Reina Sofia Hospital of Murcia, Spain
- Clinical Pharmacokinetics and Applied Pharmacotherapy Group, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Spain
| | | | - José Gil-Almela
- Department of Hospital Pharmacy, Reina Sofia Hospital of Murcia, Spain
| | - Elena Urbieta-Sanz
- Department of Hospital Pharmacy, Reina Sofia Hospital of Murcia, Spain
- Department of Pharmacology, School of Medicine, University of Murcia, Spain; and
- Clinical Pharmacokinetics and Applied Pharmacotherapy Group, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Spain
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Kimura K, Yoshida A. A prediction method for the individual serum concentration and therapeutic effect for optimizing adalimumab therapy in inflammatory bowel disease. J Pharm Pharmacol 2025; 77:299-307. [PMID: 39010700 DOI: 10.1093/jpp/rgae092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 06/24/2024] [Indexed: 07/17/2024]
Abstract
OBJECTIVES Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM's effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase. METHODS We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect. RESULTS Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient's final time point matched the observed effects in 9 of the 11 patients. CONCLUSION This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.
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Affiliation(s)
- Koji Kimura
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Atsushi Yoshida
- Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital, 6-2-24 Ofuna, Kamakura, Kanagawa 247-0056, Japan
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Minichmayr IK, Dreesen E, Centanni M, Wang Z, Hoffert Y, Friberg LE, Wicha SG. Model-informed precision dosing: State of the art and future perspectives. Adv Drug Deliv Rev 2024; 215:115421. [PMID: 39159868 DOI: 10.1016/j.addr.2024.115421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/19/2024] [Accepted: 08/01/2024] [Indexed: 08/21/2024]
Abstract
Model-informed precision dosing (MIPD) stands as a significant development in personalized medicine to tailor drug dosing to individual patient characteristics. MIPD moves beyond traditional therapeutic drug monitoring (TDM) by integrating mathematical predictions of dosing and considering patient-specific factors (patient characteristics, drug measurements) as well as different sources of variability. For this purpose, rigorous model qualification is required for the application of MIPD in patients. This review delves into new methods in model selection and validation, also highlighting the role of machine learning in improving MIPD, the utilization of biosensors for real-time monitoring, as well as the potential of models integrating biomarkers for efficacy or toxicity for precision dosing. The clinical evidence of TDM and MIPD is discussed for various medical fields including infection medicine, oncology, transplant medicine, and inflammatory bowel diseases, thereby underscoring the role of pharmacokinetics/pharmacodynamics and specific biomarkers. Further research, particularly randomized clinical trials, is warranted to corroborate the value of MIPD in enhancing patient outcomes and advancing personalized medicine.
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Affiliation(s)
- I K Minichmayr
- Dept. of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - E Dreesen
- Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - M Centanni
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Z Wang
- Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Y Hoffert
- Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - L E Friberg
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - S G Wicha
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany.
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Elford AT, Bishara M, Plevris N, Gros B, Constantine-Cooke N, Goodhand J, Kennedy NA, Ahmad T, Lees CW. Real-world effectiveness of upadacitinib in Crohn's disease: a UK multicentre retrospective cohort study. Frontline Gastroenterol 2024; 15:297-304. [PMID: 38903490 PMCID: PMC11187394 DOI: 10.1136/flgastro-2024-102668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/26/2024] [Indexed: 06/22/2024] Open
Abstract
Background Upadacitinib is a Janus kinase inhibitor, which has recently been approved for treating Crohn's disease. There are limited real-world studies on the outcomes of upadacitinib in Crohn's disease. Objective Our aim was to evaluate the outcomes of upadacitinib in a real-world Crohn's disease cohort. Methods We conducted a retrospective, multicentre, cohort study over a 2-year period across National Health Service (NHS) Lothian and Royal Devon University Healthcare NHS Foundation Trust. The primary outcome was treatment persistence at week 24. Secondary endpoints were corticosteroid-free clinical remission (Harvey-Bradshaw Index (HBI)<5) and biomarker remission (C-reactive protein (CRP)≤5 mg/L and faecal calprotectin (FCAL)<250 µg/g) at 12, 24 and 52 weeks. We recorded adverse events. Results 135 patients commenced upadacitinib as of the 1 January 2024, of which 93 patients with active Crohn's disease were included with a minimum of 12 weeks follow-up. The median follow-up time was 25 weeks (IQR 15-42 weeks). 82% of the cohort had exposure to at least two classes of advanced therapies, and 52% had exposure to at least three classes of advanced therapies. Treatment persistence was 87.1% at week 12, 81.7% at week 24 and 62.8% at week 52. Rates of clinical remission were 64% (42/66), 48% (22/46) and 38% (8/21) at weeks 12, 24 and 52, respectively. Significant reductions in HBI, CRP and FCAL were observed during follow-up. 14% (13/91) had a hospitalisation due to Crohn's disease. Adverse events occurred in 40% (37/93) of the cohort, of which 12% (11/93) were serious. Conclusion Upadacitinib was effective in a real-world, highly refractory, Crohn's disease cohort with good persistence.
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Affiliation(s)
- Alexander Thomas Elford
- Edinburgh IBD Unit, Western General Hospital, Edinburgh, Scotland, UK
- The University of Melbourne, Melbourne, Victoria, Australia
| | - Maria Bishara
- Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Nikolas Plevris
- Edinburgh IBD Unit, Western General Hospital, Edinburgh, Scotland, UK
| | - Beatriz Gros
- Edinburgh IBD Unit, Western General Hospital, Edinburgh, Scotland, UK
- Department of Gastroenterology and Hepatology, Reina Sofia Univeristy Hospital, Cordoba, Spain
| | - Nathan Constantine-Cooke
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Univeristy of Edinburgh, Edinburgh, UK
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - James Goodhand
- Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Nicholas A Kennedy
- Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
- Exeter Biomedical Research Centre, University of Exeter, Exeter, UK
| | - Tariq Ahmad
- Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Charlie W Lees
- Edinburgh IBD Unit, Western General Hospital, Edinburgh, Scotland, UK
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Nigam GB, Chatten K, Sharara A, Al-Taweel T, Alharbi O, Elamin H, Al Awadhi S, Annese V, Limdi JK. Attitudes, perceptions and barriers in implementing therapeutic drug monitoring for anti-TNFs in inflammatory bowel disease: a survey from the Middle East. Therap Adv Gastroenterol 2024; 17:17562848241230902. [PMID: 38406794 PMCID: PMC10894550 DOI: 10.1177/17562848241230902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 01/17/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND A growing body of evidence underscores the beneficial impact of therapeutic drug monitoring (TDM) on the efficacy and cost-effectiveness of anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD). OBJECTIVES We surveyed clinician attitudes, perceptions and barriers related to TDM in IBD in the Middle East. DESIGN A 15-question survey was distributed through national gastroenterological societies in five Middle Eastern countries (UAE, Saudi Arabia, Kuwait, Lebanon and Egypt). METHODS Data on clinician characteristics, demographics, utilization patterns and obstacles related to the adoption of TDM with anti-TNFs were gathered. Logistic regression analysis was used to predict factors influencing the utilization of TDM. RESULTS Among 211 respondents (82% male), 82% were consultants, 8% were physicians with an interest in gastroenterology (GI), and 6% were GI trainees. Of these, 152 met inclusion criteria, treating >5 IBD patients per month and ⩾1 with an anti-TNF per month. TDM was used in clinical practice by 78% (95% CI: 71-85) of respondents. TDM was utilized following the loss of response (LOR) in 93%, for primary non-response (PNR) in 40% and before restarting anti-TNF therapy after a drug holiday in 33% of respondents, while 34% used TDM proactively. No specific factors were associated with the use of TDM. Barriers to TDM use included cost (85%), time lag to results (71%) and lack of insurance reimbursement (65%). Overall knowledge of TDM (70%), interpretation and actioning of results (76%) or awareness of clinical guidelines (57%) were not perceived as barriers. If barriers were removed, 95% would use TDM more frequently; 93% for LOR, 60% for PNR, 50% when restarting after a drug holiday, and 54% would use TDM proactively. CONCLUSION Most gastroenterologists use TDM for LOR, with cost, time lag and insurance reimbursement being significant barriers. Addressing these barriers would increase the judicious use of reactive and proactive TDM to optimize anti-TNF therapy in IBD.
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Affiliation(s)
- Gaurav B. Nigam
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Kelly Chatten
- Northern Care Alliance NHS Foundation Trust, Bury, UK
| | - Ala Sharara
- Division of Gastroenterology and Hepatology, American University of Beirut Medical Center, Beirut, Lebanon
- Duke University Medical Center, Durham, NC, USA
| | - Talal Al-Taweel
- Division of Gastroenterology, Department of Internal Medicine, Jaber Al-Ahmad Hospital, Ministries Area, Kuwait
| | | | | | | | - Vito Annese
- Fakeeh University Hospital, Dubai, United Arab Emirates
- Vita-Salute San Raffaele University, Milan, Italy
- IRCCS San Donato Polyclinic, Milan, Italy
| | - Jimmy K. Limdi
- Northern Care Alliance NHS Foundation Trust, Fairfield General Hospital, Rochdale Old Road, Bury, Greater Manchester BL9 7TD, UK
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
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van Hoeve K, Thomas D, Hillary T, Hoffman I, Dreesen E. Identifying risk factors of anti-TNF induced skin lesions and other adverse events in paediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2024; 78:95-104. [PMID: 38291690 DOI: 10.1002/jpn3.12066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 10/27/2023] [Accepted: 11/02/2023] [Indexed: 02/01/2024]
Abstract
OBJECTIVES While higher infliximab (IFX) trough concentrations (TCs) are associated with better outcomes in patients with inflammatory bowel disease (IBD), they could pose a risk for adverse events (AEs), including IFX-induced skin lesions. Therefore, we studied correlations between IFX TCs and occurrence of AEs in paediatric IBD patients. METHODS In this single-centre study, all children with Crohn's disease (CD) and ulcerative colitis (UC) receiving IFX maintenance therapy who underwent proactive drug monitoring between March 2015 and August 2022 were included. IFX doses/intervals/TCs and patient characteristics were systematically registered, as well as AEs and skin lesions appearance. RESULTS A total of 109 patients (72 CD and 37 UC) contributed 2913 IFX TCs. During a median follow-up of 3.0 [1.5-4.5] years, we observed 684 AEs in 101 patients and 49 skin lesions in 35 patients. There was no significant difference (p = .467) in median TCs between patients with and without skin lesions. However, higher median IFX doses were associated with an increased hazard rate of skin lesions [HR 1.084 (1.024-1.148), p = .005], in addition to female sex [2.210 (1.187-5.310), p = .016] and diagnosis of CD [1.695 (1.241-1.877), p = .011]. Considering IFX therapeutic TC cut-offs of 5.0 and 9.0 µg/mL, there was no significant difference in AE rate (p = .749 and p = .833, respectively). Also, no significant association between IFX doses and AE rate (p = .159). CONCLUSIONS Increasing the IFX dose to achieve therapeutic TCs may not increase the overall risk of AEs in paediatric IBD patients. However, concerns arise regarding the risk of skin lesions, especially in female CD patients.
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Affiliation(s)
- Karen van Hoeve
- Department of Paediatric gastroenterology & Hepatology & Nutrition, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Debby Thomas
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Tom Hillary
- Department of Dermatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Ilse Hoffman
- Department of Paediatric gastroenterology & Hepatology & Nutrition, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
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Martins CDA, de Azevedo MFC, Carlos AS, Damião AOMC, Sobrado Junior CW, Nahas SC, Queiroz NSF. Predictive factors of response to infliximab therapy in Brazilian inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231210053. [PMID: 38026104 PMCID: PMC10652804 DOI: 10.1177/17562848231210053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 10/10/2023] [Indexed: 12/01/2023] Open
Abstract
Background Biological therapies have revolutionized the treatment of patients with inflammatory bowel disease (IBD). Infliximab (IFX) has been shown to be effective in inducing and maintaining remission in patients with Crohn's disease and ulcerative colitis. However, about one-third of the patients are primary non-responders, and up to half can lose response over time. Hence, it is important to assess which factors are related to treatment failure. Objectives We aimed to identify factors predicting clinical and endoscopic remission with IFX treatment during maintenance therapy in a Brazilian IBD referral center. Design We conducted a cross-sectional study to describe demographic, clinical, and IBD therapy-related characteristics of IBD patients treated with IFX for at least 6 months in a Brazilian referral center. Subsequently, we evaluated factors associated with clinical and endoscopic remission (primary and secondary outcomes, respectively). Methods We used descriptive statistics to summarize the essential demographic and clinical characteristics of the population. The association of sociodemographic and clinical variables with outcomes was analyzed using multivariable logistic regression. Results A total of 131 IBD patients (the mean age 41.7 years) were enrolled in this study. Clinical and endoscopic remission were observed in 79.4% and 58.2% of the patients, respectively. In the multivariable analysis, IFX therapy duration and higher albumin levels increased the likelihood of clinical remission, while previous surgery decreased its chance. Prior use of adalimumab and higher C-reactive protein levels reduced the likelihood of endoscopic remission. Conclusion In summary, this study has enhanced our understanding of the predictive factors of treatment response to IFX in a well-characterized Brazilian IBD population. Trial registration 4.254.501 and 2.903.748.
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Affiliation(s)
- Camilla de Almeida Martins
- Department of Gastroenterology and Division of Colorectal Surgery, University of Sao Paulo School of Medicine, São Paulo, Brazil
| | | | - Alexandre Sousa Carlos
- Department of Gastroenterology and Division of Colorectal Surgery, University of Sao Paulo School of Medicine, São Paulo, Brazil
| | | | - Carlos Walter Sobrado Junior
- Department of Gastroenterology and Division of Colorectal Surgery, University of Sao Paulo School of Medicine, São Paulo, Brazil
| | - Sergio Carlos Nahas
- Department of Gastroenterology and Division of Colorectal Surgery, University of Sao Paulo School of Medicine, São Paulo, Brazil
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Marquez-Megias S, Nalda-Molina R, Más-Serrano P, Ramon-Lopez A. Population Pharmacokinetic Model of Adalimumab Based on Prior Information Using Real World Data. Biomedicines 2023; 11:2822. [PMID: 37893195 PMCID: PMC10604709 DOI: 10.3390/biomedicines11102822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/14/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Adalimumab is a fully human monoclonal antibody used for the treatment of inflammatory bowel disease (IBD). Due to its considerably variable pharmacokinetics and the risk of developing antibodies against adalimumab, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to develop a population pharmacokinetic (PopPK) model of adalimumab for patients with IBD based on a literature model (reference model) to be used in the clinical setting. A retrospective observational study with 54 IBD patients was used to develop two different PopPK models based on the reference model. One of the developed models estimated the pharmacokinetic population parameters (estimated model), and the other model incorporated informative priors (prior model). The models were evaluated with bias and imprecision. Clinical impact was also assessed, evaluating the differences in dose interventions. The developed models included the albumin as a continuous covariate on apparent clearance. The prior model was superior to the estimated model in terms of bias, imprecision and clinical impact on the target population. In conclusion, the prior model adequately characterized adalimumab PK in the studied population and was better than the reference model in terms of predictive performance and clinical impact.
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Affiliation(s)
- Silvia Marquez-Megias
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (A.R.-L.)
| | - Ricardo Nalda-Molina
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (A.R.-L.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain
| | - Patricio Más-Serrano
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (A.R.-L.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain
- Clinical Pharmacokinetics Unit, Pharmacy Department, Alicante University General Hospital, 03010 Alicante, Spain
| | - Amelia Ramon-Lopez
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (A.R.-L.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain
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Yi ZM, Li X, Wang Z, Qin J, Jiang D, Tian P, Yang P, Zhao R. Status and Quality of Guidelines for Therapeutic Drug Monitoring Based on AGREE II Instrument. Clin Pharmacokinet 2023; 62:1201-1217. [PMID: 37490190 DOI: 10.1007/s40262-023-01283-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/26/2023]
Abstract
BACKGROUND With the progress of therapeutic drug monitoring (TDM) technology and the development of evidence-based medicine, many guidelines were developed and implemented in recent decades. OBJECTIVE The aim was to evaluate the current status of TDM guidelines and provide suggestions for their development and updates based on Appraisal of Guidelines for Research and Evaluation (AGREE) II. METHODS The TDM guidelines were systematically searched for among databases including PubMed, Embase, China National Knowledge Infrastructure, Wanfang Data, and the Chinese biomedical literature service system and the official websites of TDM-related associations. The search period was from inception to 6 April 2023. Four researchers independently screened the literature and extracted data. Any disagreement was discussed and reconciled by another researcher. The quality of guidelines was assessed using the AGREE II instrument. RESULTS A total of 92 guidelines were included, including 57 technical guidelines, three management guidelines, and 32 comprehensive guidelines. The number of TDM guidelines has gradually increased since 1979. The United States published the most guidelines (20 guidelines), followed by China (15 guidelines) and the United Kingdom (ten guidelines), and 23 guidelines were developed by international organizations. Most guidelines are aimed at adult patients only, while 28 guidelines include special populations. With respect to formulation methods, there are 23 evidence-based guidelines. As for quality evaluation results based on AGREE II, comprehensive guidelines scored higher (58.16%) than technical guidelines (51.36%) and administrative guidelines (50.00%). CONCLUSION The number of TDM guidelines, especially technical and comprehensive ones, has significantly increased in recent years. Most guidelines are confronted with the problems of unclear methodology and low quality of evidence according to AGREE II. More evidence-based research on TDM and high-quality guideline development is recommended to promote individualized therapy.
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Affiliation(s)
- Zhan-Miao Yi
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
| | - Xinya Li
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Zhitong Wang
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
| | - Jiguang Qin
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Dan Jiang
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Panhui Tian
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Ping Yang
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
| | - Rongsheng Zhao
- Department of Pharmacy, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China.
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China.
- Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China.
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10
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Serrano-Díaz L, Iniesta-Navalón C, Gómez-Espín R, Nicolás-de Prado I, Bernal-Morell E, Rentero-Redondo L. Impact of proactive therapeutic drug monitoring of infliximab during the induction phase in IBD patients. A Bayesian approach. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 115:435-443. [PMID: 36562529 DOI: 10.17235/reed.2022.8781/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND OBJECTIVES there is increasing evidence that proactive therapeutic drug monitoring in induction is useful to improve the control of inflammatory bowel disease (IBD), although it remains controversial. The primary objective of the study was to assess the short-term outcomes of proactive Bayesian therapeutic drug monitoring (TDM) during induction, to optimize infliximab (IFX) maintenance dose. METHODS retrospective observational cohort of IBD patients > 18 years. They were divided into two cohorts, standard therapy group (ST-group), with clinically based dose adjustment, and monitoring group (iTDM-group), with pharmacokinetic parameters calculated by Bayesian prediction at week 6 and individualized dosage regimens thereafter. In patients with an infliximab trough level (ITL) at week 6 below the optimal therapeutic range, the dose adjustment was performed at the first maintenance dose. RESULTS a total of 153 patients were included, 40 in the iTDM-group. Median ITL at week 6 during the induction period was 12.8 µg/ml (IRQ: 12.7) in this group. Only 16 patients (40.0 %) had ITL ≥ 15 µg/ml. Half of the patients (50.3 %) received intensified maintenance therapy during the study period (57.5 % iTDM vs 47.8 % ST, p = 0.291). The proportion of patients achieving primary response at week 14 was 51.8 %. When comparing the two groups, this proportion was higher in the iTDM group (74.3 % vs 44.2 %, p = 0.002). With regards to the variable "poor clinical outcomes" at week 26, this proportion was lower in the iTDM group (3.3 % iTDM vs 21.1 % ST, p = 0.024). CONCLUSIONS proactive therapeutic drug monitoring using Bayesian approach is associated with higher primary response rates and fewer short-term complications.
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11
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Kim ES, Kim SK, Park DI, Kim HJ, Lee YJ, Koo JS, Kim ES, Yoon H, Lee JH, Kim JW, Shin SJ, Kim HW, Kim HS, Park YS, Kim YS, Kim TO, Lee J, Choi CH, Han DS, Chun J, Kim HS. Comparison of the Pharmacokinetics of CT-P13 Between Crohn's Disease and Ulcerative Colitis. J Clin Gastroenterol 2023; 57:601-609. [PMID: 35470308 DOI: 10.1097/mcg.0000000000001715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 03/20/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND We aimed to compare trough infliximab levels and the development of antidrug antibody (ADA) for 1 year between Crohn's disease (CD) and ulcerative colitis (UC) patients who were biologic-naive, and to evaluate their impact on clinical outcomes. METHODS This was a prospective, multicenter, observational study. Biologic-naive patients with moderate to severe CD or UC who started CT-P13, an infliximab biosimilar, therapy were enrolled. Trough drug and ADA levels were measured periodically for 1 year after CT-P13 initiation. RESULTS A total of 267 patients who received CT-P13 treatment were included (CD 168, UC 99). The rates of clinical remission (72% vs. 32.3%, P <0.001) at week 54 were significantly higher in CD than in UC. The median trough drug level (μg/mL) was significantly higher in CD than in UC up to week 14 (week 2, 18.7 vs. 14.7, P <0.001; week 6, 12.5 vs. 8.6, P <0.001; week 14, 3.4 vs. 2.5, P =0.001). The median ADA level (AU/mL) was significantly lower in CD than in UC at week 2 (6.3 vs. 6.5, P =0.046), week 30 (7.9 vs. 11.8, P =0.007), and week 54 (9.3 vs. 12.3, P =0.032). Development of ADA at week 2 [adjusted odds ratio (aOR)=0.15, P =0.026], initial C-reactive protein level (aOR=0.87, P =0.032), and CD over UC (aOR=1.92, P <0.001) were independent predictors of clinical remission at week 54. CONCLUSION Infliximab shows more favorable pharmacokinetics, including high drug trough and low ADA levels, in CD than in UC, which might result in better clinical outcomes for 1-year infliximab treatment in CD patients.
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Affiliation(s)
- Eun Soo Kim
- Department of Internal Medicine, Kyungpook National University, School of Medicine
| | - Sung Kook Kim
- Department of Internal Medicine, Kyungpook National University, School of Medicine
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine
| | - Hyo Jong Kim
- Center for Crohn's and Colitis, Kyung Hee University Hospital
| | - Yoo Jin Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu
| | - Ja Seol Koo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ansan Hospital, Korea University College of Medicine, Ansan
| | - Eun Sun Kim
- Department of Internal Medicine, Korea University College of Medicine
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam
| | - Ji Hyun Lee
- Digestive Endoscopic Center, Seoul Song Do Colorectal Hospital
| | - Ji Won Kim
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine
| | - Sung Jae Shin
- Department of Internal Medicine, Ajou University School of Medicine, Suwon
| | - Hyung Wook Kim
- Department of Internal Medicine, Pusan National University School of Medicine And Medical Research Institute
| | - Hyun-Soo Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju
| | - Young Sook Park
- Department of Internal Medicine, Eulji University School of Medicine, Eulji Hospital
| | - You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine
| | - Tae Oh Kim
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan
| | - Jun Lee
- Department of Internal Medicine, Chosun University, School of Medicine
| | - Chang Hwan Choi
- Department of Internal Medicine, College of Medicine, Chung-Ang University
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea
| | - Jaeyoung Chun
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Hyun Soo Kim
- Department of Internal Medicine, Chonnam University Medical School, Gwangju
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12
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Garcia KS, de Azevedo MFC, Carlos ADS, Barros LL, Oba J, Sobrado Junior CW, Sipahi AM, Alves ODDC, Navarro-Rodriguez T, Parra RS, Chebli JMF, Chebli LA, Flores C, Vieira A, do Ceará CDA, Queiroz NSF, Damião AOMC. Efficacy of Early Optimization of Infliximab Guided by Therapeutic Drug Monitoring during Induction-A Prospective Trial. Biomedicines 2023; 11:1757. [PMID: 37371853 PMCID: PMC10296671 DOI: 10.3390/biomedicines11061757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/09/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Therapeutic drug monitoring (TDM) during induction therapy with anti-tumor necrosis factor drugs has emerged as a strategy to optimize response to these biologics and avoid undesired outcomes related to inadequate drug exposure. This study aimed to describe clinical, biological, and endoscopic remission rates at six months in Brazilian inflammatory bowel disease (IBD) patients following a proactive TDM algorithm guided by IFX trough levels (ITL) and antibodies to IFX (ATI) levels during induction, at week six. A total of 111 IBD patients were prospectively enrolled, excluding those previously exposed to the drug. ITL ≥ 10 μg/mL was considered optimal. Patients with suboptimal ITL (<10 µg/mL) were guided according to ATI levels. Those who presented ATI ≤ 200 ng/mL underwent dose intensification in the maintenance phase, and patients with ATI > 200 ng/mL discontinued IFX. In our study, proactive TDM was associated with persistence in the IFX rate at six months of 82.9%. At that time, rates of clinical, biological, and endoscopic remission in patients under IFX treatment were 80.2%, 73.9%, and 48.1%, respectively. Applying a simplified TDM-guided algorithm during induction seems feasible and can help improve patients' outcomes in clinical practice.
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Affiliation(s)
- Karoline Soares Garcia
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo 05403-000, Brazil
| | | | - Alexandre de Sousa Carlos
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo 05403-000, Brazil
| | - Luísa Leite Barros
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo 05403-000, Brazil
| | - Jane Oba
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo 05403-000, Brazil
| | | | - Aytan Miranda Sipahi
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo 05403-000, Brazil
| | | | - Tomás Navarro-Rodriguez
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo 05403-000, Brazil
| | - Rogério Serafim Parra
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil
| | | | - Liliana Andrade Chebli
- University Hospital of the Federal University of Juiz de Fora, Juiz de Fora 36038-330, Brazil
| | - Cristina Flores
- Crohn’s and Colitis Reference Center, Rio Grande do Sul 90560-002, Brazil
| | - Andrea Vieira
- Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo 01221-010, Brazil
| | | | - Natália Sousa Freitas Queiroz
- Health Sciences Graduate Program, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil
- IBD Center, Santa Cruz Hospital, Curitiba 80420-090, Brazil
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Ikegami S, Nakamura M, Honda T, Yamamura T, Maeda K, Sawada T, Ishikawa E, Yamamoto K, Furune S, Ishikawa T, Furukawa K, Ohno E, Ishigami M, Kinoshita F, Kadota Y, Tochio T, Shimomura Y, Hirooka Y, Kawashima H. Efficacy of 1-kestose supplementation in patients with mild to moderate ulcerative colitis: A randomised, double-blind, placebo-controlled pilot study. Aliment Pharmacol Ther 2023; 57:1249-1257. [PMID: 36644995 DOI: 10.1111/apt.17387] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/21/2022] [Accepted: 12/29/2022] [Indexed: 01/17/2023]
Abstract
BACKGROUND Ulcerative colitis involves an excessive immune response to intestinal bacteria. Whether administering prebiotic 1-kestose is effective for active ulcerative colitis remains controversial. AIMS This randomised, double-blind, placebo-controlled pilot trial investigated the efficacy of 1-kestose against active ulcerative colitis. METHODS Forty patients with mild to moderate active ulcerative colitis were randomly treated with 1-kestose (N = 20) or placebo (maltose, N = 20) orally for 8 weeks in addition to the standard treatment. The Lichtiger clinical activity index and Ulcerative Colitis Endoscopic Index of Severity were determined. Faecal samples were analysed to evaluate the gut microbiome and metabolites. RESULTS The clinical activity index at week 8 was significantly lower in the 1-kestose group than in the placebo group (3.8 ± 2.7 vs. 5.6 ± 2.1, p = 0.026). Clinical remission and response rates were higher in the 1-kestose group than in the placebo group (remission: 55% vs. 20%, p = 0.048; response: 60% vs. 25%, p = 0.054). The Ulcerative Colitis Endoscopic Index of Severity at week 8 was not significantly different (2.8 ± 1.6 vs. 3.5 ± 1.6, p = 0.145). Faecal analysis showed significantly reduced alpha-diversity in the 1-kestose group, with a decreased relative abundance of several bacteria, including Ruminococcus gnavus group. The short-chain fatty acid levels were not significantly different between the groups. The incidence of adverse events was comparable between the groups. DISCUSSION Oral 1-kestose is well tolerated and provides clinical improvement for patients with mild to moderate ulcerative colitis through modulation of the gut microbiome.
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Affiliation(s)
- Shuji Ikegami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Yamamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keiko Maeda
- Department of Endoscopy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsunaki Sawada
- Department of Endoscopy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Eri Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Furune
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuhiro Furukawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Eizaburo Ohno
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumie Kinoshita
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | | | | | - Yoshiharu Shimomura
- Department of Food and Nutritional Sciences, College of Bioscience and Biotechnology, Chubu University, Kasugai, Japan
| | - Yoshiki Hirooka
- Department of Liver, Biliary Tract, and Pancreas Diseases, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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14
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Bacsur P, Matuz M, Resál T, Miheller P, Szamosi T, Schäfer E, Sarlós P, Iliás Á, Szántó K, Rutka M, Bálint A, Milassin Á, Fábián A, Bor R, Szepes Z, Molnár T, Farkas K. Ustekinumab is associated with superior treatment persistence but not with higher remission rates versus vedolizumab in patients with refractory Crohn's disease: results from a multicentre cohort study. Therap Adv Gastroenterol 2022; 15:17562848221144349. [PMID: 36600684 PMCID: PMC9806440 DOI: 10.1177/17562848221144349] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/23/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Treatment with antitumor necrosis factor alpha (anti-TNF-α) is safe and effective as first-line therapy; however, its efficacy is limited due to primary nonresponse (PNR) and secondary loss of response (LOR), resulting in treatment discontinuation in approximately 40%-50% of cases. Vedolizumab (VDZ) and ustekinumab (UST) therapies could be good alternatives in patient with anti-TNF failure; however, no head-to-head randomized comparison of these drugs as second- or third-line treatments has been made. OBJECTIVES This study aimed to assess the treatment persistence and comparative effectiveness of UST and VDZ in patients with refractory Crohn's disease (CD). DESIGN In this nationwide retrospective study, patients with CD on UST or VDZ maintenance therapy were enrolled. Clinical data at baseline, after induction, and at week 52 were obtained. METHODS Clinical and biochemical activities as well as corticosteroid-free remission (SFR) rates were assessed, while concomitant medications, comorbidities, hospitalizations, and surgeries were recorded during the follow-up to detect any predictors. RESULTS A total of 161 UST- and 65 VDZ-treated patients completed the follow-up. No significant difference in clinical or biochemical remission rates was observed after induction between the two treatment groups; however, clinical remission rate at week 52 was higher in UST group. UST showed superior drug persistence than VDZ (86.5%, 57.9%, p < 0.0001). The drug type was predictive of clinical SFR at week 52 [p = 0.011, odds ratio (OR) = 2.39 with UST]. Drug failure rates were higher for VDZ than those for UST (PNR rates: 21.54% and 4.97%, respectively, p < 0.001, OR = 8.267, p = 0.001). LOR and escalations were more common during UST treatment (61.5% versus 36.9%, p < 0.001; 64.2% versus 23.1%, p < 0.001). Hospital and surgical admission rates did not differ significantly. Only one adverse event occurred with VDZ at week 20, which led to drug cessation. CONCLUSIONS VDZ and UST were safe and effective for treating patients with CD in whom anti-TNF therapy failed. UST showed superior drug persistence than VDZ, but dose escalation was more frequent. Biologicals used in lower treatment lines resulted in better drug persistence.
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Affiliation(s)
- Péter Bacsur
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Mária Matuz
- Institute of Clinical Pharmacy, Faculty of
Pharmacy, University of Szeged, Szeged, Hungary
| | - Tamás Resál
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Pál Miheller
- Department of Surgery and Interventional
Gastroenterology, Faculty of Medicine, Semmelweis University, Budapest,
Hungary
| | - Tamás Szamosi
- Department of Gastroenterology, Military
Hospital – State Health Centre, Budapest, Hungary
| | - Eszter Schäfer
- Department of Gastroenterology, Military
Hospital – State Health Centre, Budapest, Hungary
| | - Patrícia Sarlós
- Division of Gastroenterology, First Department
of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Ákos Iliás
- First Department of Medicine, Faculty of
Medicine, Semmelweis University, Budapest, Hungary
| | - Kata Szántó
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Mariann Rutka
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Anita Bálint
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Ágnes Milassin
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Anna Fábián
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Renáta Bor
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Zoltán Szepes
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Molnár
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Szeged, Hungary
| | - Klaudia Farkas
- Department of Medicine, Albert Szent-Györgyi
Medical School, University of Szeged, Kálvária Ave. 57, Szeged H-6720,
Hungary
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15
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Higher serum infliximab concentrations during induction predict short-term endoscopic response in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2022; 34:1125-1131. [PMID: 36170681 DOI: 10.1097/meg.0000000000002431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Measuring of serum infliximab (IFX) induction concentrations might reduce primary non-response rates in inflammatory bowel diseases (IBD), but optimal target concentrations are unclear. We investigated whether IFX induction concentrations predict short-term endoscopic response at week 12 or treatment persistence at week 52. METHODS Sixty-nine IBD patients (Crohn's disease, n=24; ulcerative colitis, n=45) received standard IFX induction of 5 mg/kg bodyweight at weeks 0, 2, and 6. Responders continued maintenance therapy and underwent follow-up until week 52 or treatment discontinuation. We measured IFX concentrations at weeks 2, 6, and 12, and evaluated treatment response around week 12 with endoscopy or with clinical scores and fecal calprotectin. Using the receiver operating characteristic analysis, we determined optimal IFX concentration thresholds associated with treatment response. We further compared IFX induction concentrations between patients persisting on IFX at week 52 and patients discontinuing treatment due to insufficient response. RESULTS Responders (74%, 51 out of 69 patients) had significantly higher median IFX concentrations than non-responders at weeks 6 (25.06 vs. 19.68 µg/ml; P = 0.04) and 12 (18.03 vs. 10.02 µg/ml; P = 0.03), but not at week 2 (33.12 vs. 34.20 µg/ml; P = 0.97). Optimal IFX concentration thresholds for induction response were 21.33 and 5.13 µg/ml at weeks 6 and 12, respectively. Fifty-three patients continued IFX maintenance therapy until week 52. Induction concentrations failed to predict persistence on IFX therapy at week 52. CONCLUSION Higher IFX induction concentrations predict endoscopic short-term response. However, induction concentrations failed to predict long-term persistence on IFX treatment.
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16
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Dubinsky MC, Mendiolaza ML, Phan BL, Moran HR, Tse SS, Mould DR. Dashboard-Driven Accelerated Infliximab Induction Dosing Increases Infliximab Durability and Reduces Immunogenicity. Inflamm Bowel Dis 2022; 28:1375-1385. [PMID: 34978325 DOI: 10.1093/ibd/izab285] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Accelerated infliximab (IFX) induction is often based on clinical parameters as opposed to pharmacokinetics (PK). We aimed to investigate the impact of dashboard-guided optimized induction dosing on IFX durability and immunogenicity in a real-world inflammatory bowel disease (IBD) setting. METHODS Pediatric and adult IBD patients were enrolled in a prospective single arm intervention trial. Cumulative data from each infusion (INF), weight, albumin, C-reactive protein, IFX dose, IFX trough level, and antidrug antibody presence were used to inform subsequent INF dosing. Forecasts driven by adaptive Bayesian modeling were generated to maintain trough levels for the third (INF3) and fourth (INF4) infusions of 17 μg/mL and 10 μg/mL, respectively. The primary outcome was proportion of patients prescribed accelerated dosing (AD) intervals by INF3 (<22 days) or INF4 (<49 days). Secondary outcomes included week 52 clinical and PK outcomes. Multivariate analyses and Kaplan-Meier curves compared outcomes based on adherence to dashboard forecasts. RESULTS Of the 180 per-protocol population, AD was forecast for 41% (INF3) and 69% (INF4) of patients with median intervals of 17 (INF3) and 39 (INF4) days. Baseline age >18 years, albumin >3.5 g/L, and 10-mg/kg dose were independently associated with lower rates of AD by INF4. Nonadherence with the INF4 forecast (n = 39) was an independent predictor of antidrug antibody (P < .0001) and IFX discontinuation (P = .0006). A total of 119 of 123 patients on IFX at week 52 were in steroid-free remission. CONCLUSIONS The application of a PK dashboard during induction can optimize dosing early to improve IFX durability and immunogenicity.
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Affiliation(s)
- Marla C Dubinsky
- Department of Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michelle L Mendiolaza
- Department of Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Becky L Phan
- Department of Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hunter R Moran
- Department of Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stacy S Tse
- Department of Pediatrics, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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17
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Gottlieb ZS, Dolinger M, Kayal M, Rao BB, Bhattacharya A, Dubinsky MC, Ungaro RC. Clinical Challenge: Proactive Precise Management of Active Ulcerative Colitis During Pregnancy-Advantages of Point-of-Care Intestinal Ultrasound and Therapeutic Drug Monitoring. Dig Dis Sci 2022; 67:3557-3561. [PMID: 35579797 DOI: 10.1007/s10620-022-07532-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Zoë S Gottlieb
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
| | - Michael Dolinger
- Departments of Pediatrics and Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Maia Kayal
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Bhavana Bhagya Rao
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Abhik Bhattacharya
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marla C Dubinsky
- Departments of Pediatrics and Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Ryan C Ungaro
- Division of Gastroenterology, Department of Medicine, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
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18
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Martins CDA, Garcia KS, Queiroz NSF. Multi-utility of therapeutic drug monitoring in inflammatory bowel diseases. Front Med (Lausanne) 2022; 9:864888. [PMID: 35966848 PMCID: PMC9366431 DOI: 10.3389/fmed.2022.864888] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 07/04/2022] [Indexed: 11/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) treatment targets have progressed over time from clinical response to clinical and endoscopic remission. Several data have shown a positive correlation between serum biologic drug concentrations and favorable therapeutic outcomes. Therapeutic drug monitoring (TDM) has evolved as an important approach for optimizing the use of immunobiologics, especially antitumor necrosis factor therapy, in patients with IBD. The use of TDM is supported by medical societies and IBD experts in different contexts; however, challenges remain due to knowledge gaps that limit the widespread use of it. The aim of this review is to assess the role of TDM in IBD, focusing on the implementation of this strategy in different scenarios and demonstrating the multi-utility aspects of this approach in clinical practice.
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Affiliation(s)
| | - Karoline Soares Garcia
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
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19
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Marsal J, Barreiro-de Acosta M, Blumenstein I, Cappello M, Bazin T, Sebastian S. Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front Med (Lausanne) 2022; 9:897936. [PMID: 35783628 PMCID: PMC9241563 DOI: 10.3389/fmed.2022.897936] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/25/2022] [Indexed: 11/30/2022] Open
Abstract
Anti-tumor necrosis factor (anti-TNF) therapy has been successfully used as first-line biologic treatment for moderate-to-severe inflammatory bowel disease (IBD), in both "step-up" and "top-down" approaches, and has become a cornerstone of IBD management. However, in a proportion of patients the effectiveness of anti-TNF therapy is sub-optimal. Either patients do not achieve adequate initial response (primary non-response) or they lose response after initial success (loss of response). Therapeutic drug monitoring determines drug serum concentrations and the presence of anti-drug antibodies (ADAbs) and can help guide treatment optimization to improve patient outcomes. For patients with low drug concentrations who are ADAb-negative or display low levels of ADAbs, dose escalation is recommended. Should response remain unchanged following dose optimization the question whether to switch within class (anti-TNF) or out of class (different mechanism of action) arises. If ADAb levels are high and the patient has previously benefited from anti-TNF therapy, then switching within class is a viable option as ADAbs are molecule specific. Addition of an immunomodulator may lead to a decrease in ADAbs and a regaining of response in a proportion of patients. If a patient does not achieve a robust therapeutic response with an initial anti-TNF despite adequate drug levels, then switching out of class is appropriate. In conjunction with the guidance above, other factors including patient preference, age, comorbidities, disease phenotype, extra-intestinal manifestations, and treatment costs need to be factored into the treatment decision. In this review we discuss current evidence in this field and provide guidance on therapeutic decision-making in clinical situations.
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Affiliation(s)
- Jan Marsal
- Department of Gastroenterology, Skåne University Hospital, Lund/Malmö, Sweden
- Department of Immunology, Lund University, Lund, Sweden
| | - Manuel Barreiro-de Acosta
- Gastroenterology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
| | - Irina Blumenstein
- Department of Internal Medicine 1, Gastroenterology, Hepatology and Clinical Nutrition, University Clinic Frankfurt, Frankfurt, Germany
| | - Maria Cappello
- Gastroenterology and Hepatology Section, Promise, University of Palermo, Palermo, Italy
| | - Thomas Bazin
- Department of Gastroenterology, Université Paris Saclay/UVSQ, INSERM, Infection and Inflammation, UMR 1173, AP-HP, Hôpital Ambroise Paré, Boulogne Billancourt, France
| | - Shaji Sebastian
- Inflammatory Bowel Disease (IBD) Unit, Hull University Teaching Hospitals National Health Service (NHS) Trust, Hull, United Kingdom
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20
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Cogan RC, El-Matary BW, El-Matary WM. Therapeutic drug monitoring for biological medications in inflammatory bowel disease. Saudi J Gastroenterol 2022; 28:322-331. [PMID: 35343213 PMCID: PMC9752529 DOI: 10.4103/sjg.sjg_3_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Therapeutic drug monitoring (TDM) is the measurement of serum drug concentrations and anti-drug-antibodies (ADA) for biologic therapies used to treat inflammatory bowel disease (IBD). The aim of this article is to review the current literature concerning reactive and proactive TDM for both adults and children with IBD. Although optimal trough concentration windows for some of these medications are not well defined, there is mounting evidence to suggest that reactive TDM is associated with favorable therapeutic outcomes, including less immunogenicity, greater drug exposure, and a decreased risk of treatment failure. Moreover, while the exact mechanism of loss of response is not fully elucidated, the vast majority of studies have reported a decreased incidence of nonresponse and secondary loss of response when TDM is implemented. Proactive TDM, while even less understood in the literature, employs a schedule of preemptive analysis of serum trough concentrations to accordingly adjust the patient's biologic dosage. Proactive TDM may decrease the need for IBD-related surgery/hospitalization, and therefore merits future studies of investigation.
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Affiliation(s)
- Rachel C. Cogan
- Section of Pediatric Gastroenterology, Department of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Basem W. El-Matary
- Section of Pediatric Gastroenterology, Department of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Wael M. El-Matary
- Section of Pediatric Gastroenterology, Department of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada,Address for correspondence: Dr. Wael M. El-Matary, Professor of Pediatric and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, AE 408 Children's Hospital, Health Sciences Centre, 840 Sherbrook St., Winnipeg, Manitoba, R3A 1S1, Canada. E-mail:
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21
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Raine T, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, Bachmann O, Bettenworth D, Chaparro M, Czuber-Dochan W, Eder P, Ellul P, Fidalgo C, Fiorino G, Gionchetti P, Gisbert JP, Gordon H, Hedin C, Holubar S, Iacucci M, Karmiris K, Katsanos K, Kopylov U, Lakatos PL, Lytras T, Lyutakov I, Noor N, Pellino G, Piovani D, Savarino E, Selvaggi F, Verstockt B, Spinelli A, Panis Y, Doherty G. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis 2022; 16:2-17. [PMID: 34635919 DOI: 10.1093/ecco-jcc/jjab178] [Citation(s) in RCA: 514] [Impact Index Per Article: 171.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Hamburg, Lüneburg, Germany
| | - Michel Adamina
- Department of Surgery, Clinic of Visceral and Thoracic Surgery, Cantonal Hospital Winterthur, Zurich, Switzerland
- Department of Biomedical Engineering, Clinical Research and Artificial Intelligence in Surgery, Faculty of Medicine, University of Basel, Allschwil, Switzerland
| | - Vito Annese
- Department of Gastroenterology, Fakeeh University Hospital, Dubai, UAE
| | - Oliver Bachmann
- Department of Internal Medicine I, Siloah St. Trudpert Hospital, Pforzheim; Hannover Medical School, Hannover, Germany
| | - Dominik Bettenworth
- University Hospital Munster, Department of Medicine B - Gastroenterology and Hepatology, Munster, Germany
| | - Maria Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Wladyslawa Czuber-Dochan
- King's College London, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, London, UK
| | - Piotr Eder
- Department of Gastroenterology, Dietetics and Internal Medicine - Poznań University of Medical Sciences; Heliodor Święcicki University Hospital, Poznań, Poland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Catarina Fidalgo
- Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
| | - Gionata Fiorino
- Department of Biomedical Sciences, Humanitas University; IBD Center, Humanitas Clinical and Research Center, Milan, Italy
| | - Paolo Gionchetti
- IBD Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna DIMEC, University of Bologna, Bologna, Italy
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, Royal London Hospital, London, UK
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna; Karolinska University Hospital, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Marietta Iacucci
- Institute of Immunology and Immunotherapy, NIHR Biomedical Research Centre, University of Birmingham; Division of Gastroenterology, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Uri Kopylov
- Department of Gastroenterology, Tel-HaShomer Sheba Medical Center, Ramat Gan, and Sackler Medical School, Tel Aviv, Israel
| | - Peter L Lakatos
- Division of Gastroenterology, McGill University Health Centre, Montreal, QC, Canada
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Theodore Lytras
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Ivan Lyutakov
- Department of Gastroenterology, University Hospital 'Tsaritsa Yoanna - ISUL', Medical University Sofia, Sofia, Bulgaria
| | - Nurulamin Noor
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Department of Advanced Medical and Surgical Sciences, Universitá degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
- Colorectal Surgery, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Daniele Piovani
- Department of Biomedical Sciences, Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Francesco Selvaggi
- Department of Advanced Medical and Surgical Sciences, Universitá degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven; Department of Chronic Diseases, Metabolism and Ageing, TARGID - IBD, Leuven, Belgium
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Yves Panis
- Department of Colorectal Surgery, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy and Université of Paris, France
| | - Glen Doherty
- Department of Gastroenterology and Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
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22
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Infliximab Concentrations during Induction Are Predictive for Endoscopic Remission in Pediatric Patients with Inflammatory Bowel Disease under Combination Therapy. J Pediatr 2022; 240:150-157.e4. [PMID: 34481805 DOI: 10.1016/j.jpeds.2021.08.079] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVES To study infliximab (IFX) pharmacokinetics in children with inflammatory bowel disease (IBD) during induction therapy to predict outcome and explore if other covariates influenced outcome. STUDY DESIGN All children with IBD starting IFX therapy (5 mg/kg at weeks 0, 2, 6, and 12) for active luminal disease from May 2017 to May 2019 were included and followed prospectively. Patients were sampled at multiple timepoints during induction (trough concentrations and peak concentration at weeks 0, 2, 6, and 12, and intermediate concentration at weeks 1-4). IFX concentrations and cumulative drug exposure were correlated with outcome at 6 months. Endoscopic remission was defined as Simple Endoscopic Score for Crohn's Disease of <3 or Mayo endoscopic subscore of 0, and deep remission as endoscopic with clinical remission (Pediatric Ulcerative Colitis Activity Index/Pediatric Crohn's Disease Activity Index of <10). RESULTS There were 252 serum induction concentrations obtained from 32 patients (81% on concomitant thiopurines). Children in endoscopic remission (all in deep remission) at 6 months had significantly higher drug concentrations from week 4 onward. A receiver operating characteristics curve analysis identified IFX trough concentrations at week 12 of ≥5.0 μg/mL and area under the curve at weeks 0-12 of ≥4056.0 μg∗day/mL as the minimal target to achieve endoscopic remission at 6 months (area under the receiver operating characteristics curve, 0.796 [95% CI, 0.62-0.97] and area under the receiver operating characteristics curve, 0.778 [95% CI, 0.61-0.94], respectively). In addition, our findings suggest that proteomic analysis may help to understand IFX response. CONCLUSIONS Higher IFX exposure during induction therapy in pediatric patients with IBD is associated with significantly better endoscopic and deep remission rates at 6 months. Drug concentrations differentiate remitters from nonremitters from week 4 after induction onward.
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23
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Shehab M, Alasfour H, Abdullah I, Alhendi G, Alhadab A, Alfadhli A, Ziyab AH, Battat R. Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study. Front Med (Lausanne) 2021; 8:801532. [PMID: 35004778 PMCID: PMC8733246 DOI: 10.3389/fmed.2021.801532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/06/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Anti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease. Methods: A nationwide multicenter retrospective cohort study was conducted by evaluating patients' charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across seven hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI). Results: In the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p < 0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab. Conclusion: In patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed.
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Affiliation(s)
- Mohammad Shehab
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Kuwait City, Kuwait
| | - Hajer Alasfour
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Israa Abdullah
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Ghadeer Alhendi
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Anwar Alhadab
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Ahmad Alfadhli
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Kuwait City, Kuwait
| | - Ali H. Ziyab
- Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Robert Battat
- Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, New York Presbyterian-Weill Cornell Medical College, New York, NY, United States
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24
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Levels of Biosimilar Infliximab during and after Induction Treatment in Crohn's Disease and Ulcerative Colitis-A Prospective Polish Population Study. J Clin Med 2021; 10:jcm10225311. [PMID: 34830598 PMCID: PMC8619897 DOI: 10.3390/jcm10225311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 11/29/2022] Open
Abstract
Background: Primary lack or secondary loss of response to therapy with infliximab is a significant problem. This study aimed to evaluate the response to treatment in patients with Crohn’s disease (CD) and ulcerative colitis (UC) achieving therapeutic and sub-therapeutic trough levels of biosimilar infliximab (CT-P13). Results: A total of 65 patients (32 with CD and 33 with UC) were recruited. The overall response rate in both CD and UC patients exceeded 80%. There were no significant differences in treatment response and CT-P13 levels for patients with CD or UC. We did not find significant differences in the percentage of patients achieving drug levels of 3 μg/mL at week 6, 10, or 12; a significant decrease was observed at week 14. Up to 55.5% of patients with CD and 64.3% of patients with UC with sub-therapeutic CT-P13 levels at week 14 primarily responded to treatment. Conclusions: Intermediate measurements of drug levels at weeks 10 and 12 did not capture any pronounced decrease in infliximab concentrations below therapeutic levels in either group, thus suggesting no clinical usefulness. A significant percentage of patients primarily responded to treatment despite sub-therapeutic drug levels after the induction phase.
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25
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Abdullah I, Alhendi G, Alhadab A, Alasfour H, Shehab M. Gastroenterologists Adherence to Tumor Necrosis Factor Antagonist Combination Therapy in Inflammatory Bowel Disease. Front Med (Lausanne) 2021; 8:725512. [PMID: 34660635 PMCID: PMC8511459 DOI: 10.3389/fmed.2021.725512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/30/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: Tumor necrosis factor antagonists (anti-TNF) therapies are used for the management of moderate to severe inflammatory bowel disease (IBD). Anti-TNF combination therapy, with immunomodulators, has been shown to reduce immunogenicity, especially for infliximab, improve treatment success rate and patient outcomes. We evaluated factors associated with gastroenterologists adherence to anti-TNF combination therapy. Methods: A retrospective cohort study was performed to evaluate the adherence of gastroenterologists (n = 14), at an inflammatory bowel disease center, to anti-TNF combination therapy. Records of patients who received Infliximab (n = 137) or adalimumab (n = 152) were obtained and their ordering physicians' data was analyzed. Gastroenterologists were divided into six groups according to their age and interest in IBD. The baseline characteristics of their patients were also obtained. Results: The proportion of patients on combination therapy in the young gastroenterologists group was higher than those in the senior gastroenterologists group for both infliximab (83.2 vs. 55.6%, respectively, P < 0.001) and adalimumab (59 vs. 30.8%, respectively, P < 0.001). Gastroenterologists with interest in inflammatory bowel disease (IBD interest group) had also more proportion of patients on adalimumab combination therapy compared to gastroenterologists with no interest in IBD (non-IBD interest group) (61.7 vs. 35.2%, respectively, P < 0.001). Gastroenterologists who were both young and have interest in IBD had more proportion of patients on combination therapy than those who were senior or had no interest in IBD for both infliximab (89.4 vs. 63.4%, respectively, P < 0.001) and adalimumab (75.9 vs. 33%, P < 0.001). The IBD interest group was also requesting more antidrug antibody level tests than those in the non-IBD interest group (41.4 vs. 12.3 tests, respectively, P < 0.001). Conclusion: Young gastroenterologists are more likely to prescribe anti-TNF infliximab and adalimumab combination therapy than senior gastroenterologists. In addition, gastroenterologists with IBD interest are more likely to prescribe adalimumab combination therapy than gastroenterologists with no IBD interest. Moreover, young gastroenterologists who have interest in IBD are more likely to prescribe both infliximab and adalimumab combination therapy than senior gastroenterologists or those with no IBD interest. In addition, gastroenterologists with IBD interest requested more anti-TNF serum drug concentrations and antidrug antibody level tests than those with no IBD interest.
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Affiliation(s)
- Israa Abdullah
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Ghadeer Alhendi
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Anwar Alhadab
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Hajer Alasfour
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Mohammad Shehab
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Kuwait City, Kuwait
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26
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Linares R, Francés R, Gutiérrez A, Juanola O. Bacterial Translocation as Inflammatory Driver in Crohn's Disease. Front Cell Dev Biol 2021; 9:703310. [PMID: 34557484 PMCID: PMC8452966 DOI: 10.3389/fcell.2021.703310] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/30/2021] [Indexed: 12/26/2022] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host–microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.
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Affiliation(s)
- Raquel Linares
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain
| | - Rubén Francés
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | - Ana Gutiérrez
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain.,Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
| | - Oriol Juanola
- Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Lugano, Switzerland.,Faculty of Biomedical Sciences, Universitá della Svizzera Italiana, Lugano, Switzerland
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27
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Marquez-Megias S, Ramon-Lopez A, Más-Serrano P, Diaz-Gonzalez M, Candela-Boix MR, Nalda-Molina R. Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease. Pharmaceutics 2021; 13:pharmaceutics13081244. [PMID: 34452204 PMCID: PMC8398570 DOI: 10.3390/pharmaceutics13081244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/03/2021] [Accepted: 08/07/2021] [Indexed: 12/11/2022] Open
Abstract
Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.
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Affiliation(s)
- Silvia Marquez-Megias
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
| | - Amelia Ramon-Lopez
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
- Correspondence:
| | - Patricio Más-Serrano
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
- Clinical Pharmacokinetics Unit, Pharmacy Department, Alicante University General Hospital, 03010 Alicante, Spain
| | - Marcos Diaz-Gonzalez
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
- Clinical Pharmacokinetics Unit, Pharmacy Department, Alicante University General Hospital, 03010 Alicante, Spain
| | | | - Ricardo Nalda-Molina
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
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28
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Vande Casteele N, Feagan BG, Wolf DC, Pop A, Yassine M, Horst SN, Ritter TE, Sandborn WJ. Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Crohn Disease: A Theoretical Construct to Apply Pharmacokinetics and Guidelines to Clinical Practice. Inflamm Bowel Dis 2021; 27:1346-1355. [PMID: 33051647 PMCID: PMC8314098 DOI: 10.1093/ibd/izaa265] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Indexed: 12/13/2022]
Abstract
Therapeutic drug monitoring (TDM) is the measurement of drug and antidrug antibody concentrations in individuals to guide treatment decisions. In patients with Crohn disease (CD), TDM, used either reactively or proactively, is emerging as a valuable tool for optimization of tumor necrosis factor (TNF) antagonist therapy. Reactive TDM is carried out in response to treatment failure, whereas proactive TDM involves the periodic monitoring of patients responding to TNF antagonist therapy to allow treatment optimization. In patients with CD, most of the available data for TDM relate to the first-to-market TNF antagonist infliximab and, to a lesser extent, to adalimumab and certolizumab pegol. Several gastroenterology associations, including the American Gastroenterology Association, have endorsed the use of reactive TDM in patients with active CD. However, fewer recommendations currently exist for the use of proactive TDM, although several new prospective randomized controlled trials evaluating proactive TDM strategies have been published. In this review, the current evidence for reactive and proactive TDM is discussed, and a proactive treatment algorithm for certolizumab pegol based on previously published threshold concentrations is proposed.
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Affiliation(s)
- Niels Vande Casteele
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | | | - Douglas C Wolf
- Atlanta Gastroenterology Associates, Atlanta, Georgia, USA
| | - Anca Pop
- UCB Pharma, Smyrna, Georgia, USA
| | | | - Sara N Horst
- Vanderbilt University, Nashville, Tennessee, USA
| | | | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
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Papamichael K, Casteele NV, Jeyarajah J, Jairath V, Osterman MT, Cheifetz AS. Higher Postinduction Infliximab Concentrations Are Associated With Improved Clinical Outcomes in Fistulizing Crohn's Disease: An ACCENT-II Post Hoc Analysis. Am J Gastroenterol 2021; 116:1007-1014. [PMID: 33929379 PMCID: PMC8095681 DOI: 10.14309/ajg.0000000000001111] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION There are only limited data regarding the role of therapeutic drug monitoring in fistulizing Crohn's disease (CD). We investigated the association between both induction and maintenance serum infliximab concentrations and favorable therapeutic outcomes in patients with fistulizing CD. METHODS This was a post hoc analysis of the ACCENT-II trial evaluating patients with fistulizing CD receiving induction (n = 282) and maintenance infliximab therapy (n = 139). Investigated therapeutic outcomes at both week 14 and week 54 included fistula response, complete fistula response, C-reactive protein (CRP) normalization (≤5 mg/L) in patients with an elevated baseline CRP, and a more stringent outcome of composite remission, defined as combined complete fistula response and CRP normalization. Associations between serum infliximab concentrations and outcomes were assessed by multivariable logistic regression models. RESULTS Higher week 14 infliximab concentrations were independently associated with week 14 fistula response (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.02-1.32; P = 0.019), and composite remission (OR: 2.32; 95% CI: 1.55-3.49; P < 0.001). Higher week 14 infliximab concentrations were also independently associated with week 54 composite remission (OR: 2.05; 95% CI: 1.10-3.82; P = 0.023). Based on receiver operating characteristic curve analysis, week 14 infliximab concentrations thresholds with combined maximal sensitivity and specificity of ≥20.2 μg/mL at week 2, ≥15 μg/mL at week 6, and ≥7.2 μg/mL at week 14 were associated with week 14 composite remission. DISCUSSION Higher post-induction infliximab concentrations are associated with early and long-term favorable therapeutic outcomes in patients with fistulizing CD.
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Affiliation(s)
- Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Niels Vande Casteele
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Robarts Clinical Trials, Inc., London, Ontario, Canada
| | | | - Vipul Jairath
- Robarts Clinical Trials, Inc., London, Ontario, Canada
- Department of Medicine, Western University, London, ON, Canada
| | - Mark T. Osterman
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Adam S. Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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Reinisch W, Gecse K, Halfvarson J, Irving PM, Jahnsen J, Peyrin-Biroulet L, Rogler G, Schreiber S, Danese S. Clinical Practice of Adalimumab and Infliximab Biosimilar Treatment in Adult Patients With Crohn's Disease. Inflamm Bowel Dis 2021; 27:106-122. [PMID: 32634212 PMCID: PMC7737159 DOI: 10.1093/ibd/izaa078] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Indexed: 12/16/2022]
Abstract
The introduction of tumor necrosis factor (TNF) inhibitors has significantly changed the treatment landscape in Crohn's disease (CD). The overall therapeutic achievements with TNF inhibitors such as infliximab, adalimumab, and certolizumab pegol paved the way to push the boundaries of treatment goals beyond symptomatic relief and toward cessation of objective signs of inflammation, including endoscopic remission. Even though these agents are widely used for the treatment of moderate to severe CD, heterogeneity still exists in translating evidence-based guidelines on the use of anti-TNF agents into actual treatment algorithms in CD. This might be due to several reasons including disparities in health expenditure policies; lack of harmonization between countries; and variations in assessment of disease severity, use of disease monitoring tools, or application of treatment targets by physicians. With the advent of biosimilars, patent-free versions of reference biologics are now available to minimize health inequalities in drug availability. In this context, this article aims to provide practical clinical guidance for the use of infliximab and adalimumab biosimilars in patients with moderate to severe CD by outlining different clinical scenarios that patients may encounter during their treatment journey.
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Affiliation(s)
- Walter Reinisch
- Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Krisztina Gecse
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Peter M Irving
- Department of Gastroenterology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK
| | - Jørgen Jahnsen
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Laurent Peyrin-Biroulet
- Department of Hepato-Gastroenterology and Inserm U954, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital, University of Zurich, Zurich, Switzerland
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
- Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
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Kapoor A, Crowley E. Advances in Therapeutic Drug Monitoring in Biologic Therapies for Pediatric Inflammatory Bowel Disease. Front Pediatr 2021; 9:661536. [PMID: 34123968 PMCID: PMC8187753 DOI: 10.3389/fped.2021.661536] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/09/2021] [Indexed: 12/19/2022] Open
Abstract
In the current era of treat-to-target strategies, therapeutic drug monitoring (TDM) has emerged as a potential tool in optimizing the efficacy of biologics for children diagnosed with inflammatory bowel disease (IBD). The incorporation of TDM into treatment algorithms, however, has proven to be complex. "Proactive" TDM is emerging as a therapeutic strategy due to a recently published pediatric RCT showing a clear benefit of "proactive" TDM in anti-TNF therapy. However, target therapeutic values for different biologics for different disease states [ulcerative colitis (UC) vs. Crohn's disease (CD)] and different periods of disease activity (induction vs. remission) require further definition. This is especially true in pediatrics where the therapeutic armamentarium is limited, and fixed weight-based dosing may predispose to increased clearance leading to decreased drug exposure and subsequent loss of response (pharmacokinetic and/or immunogenic). Model-based dosing for biologics offers an exciting insight into dose individualization thereby minimizing the chances of losing response. Similarly, point-of-care testing promises real-time assessment of drug levels and individualized decision-making. In the current clinical realm, TDM is being used to prolong drug durability and efficacy and prevent loss of response. Ongoing innovations may transform it into a personalized tool to achieve optimal therapeutic endpoints.
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Affiliation(s)
- Akshay Kapoor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, London Health Sciences Centre, Children's Hospital Western Ontario, Western University, London, ON, Canada
| | - Eileen Crowley
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, London Health Sciences Centre, Children's Hospital Western Ontario, Western University, London, ON, Canada
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Gómez Espín R, Nicolás De Prado I, Gil Candel M, González Carrión M, Rentero Redondo L, Iniesta Navalón C. Association between ustekinumab trough concentrations and biochemical outcomes in patients with Crohn's disease. A real life study. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 113:110-115. [PMID: 33213170 DOI: 10.17235/reed.2020.7124/2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
INTRODUCTION numerous studies have shown a positive correlation between serum biologic drug concentrations and favorable therapeutic outcomes during the induction and maintenance period in patients with Crohn's disease (CD). To our knowledge, only a few and contradictory studies have determined the association between ustekinumab (UST) trough concentrations and biological outcomes. This study aimed to investigate the relationship between ustekinumab trough concentrations and biological outcomes in a real-world setting. METHODS a cross-sectional cohort study was performed. All adult patients with CD who received maintenance therapy (≥ 24 weeks) with ustekinumab were included in the study. Clinical response was determined using the Harvey-Bradshaw Index. Biochemical remission was defined as a fecal calprotectin level < 150 µg/g in feces and a biochemical response as > 50 % reduction of fecal calprotectin. RESULTS a total of 58 CD patients were included in the study and the median UST trough concentration was 1.78 µg/ml (IQR: 2.56). Differences in ustekinumab trough concentrations were observed for clinical (2.25 µg/ml vs 0.65 µg/ml; p = 0.006) and biochemical remission (2.33 µg/ml vs 1.03 µg/ml; p = 0.047). According to ROC analysis, a cut-off of 1.4 µg/ml (AUC: 077) and 2.0 µg/ml (AUC: 0.65) were identified for predicting clinical and biochemical remission, respectively. Likewise, ustekinumab trough levels were also higher in "composite clinical/biochemical remission" (2.38 µg/ml vs 1.08 µg/ml; p = 0.042). The trough level that was best associated with composite clinical/biochemical remission was 2.2 µg/ml (AUC: 0.69). CONCLUSION this real-life study shows the association between ustekinumab trough concentration and clinical and biochemical remission and we suggest an optimal cut-off point higher than 2.2 µg/ml. Further studies are needed to confirm the findings and to identify the optimal cut-off in different disease outcomes and disease phenotypes.
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Queiroz NSF, Teixeira FV, Parra RS, Kotze PG. INDUCTION THERAPEUTIC DRUG MONITORING REGIMEN WITH INFLIXIMAB: A SIMPLIFIED EVIDENCE-BASED ALGORITHM FOR INFLAMMATORY BOWEL DISEASE. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:507-510. [PMID: 33331484 DOI: 10.1590/s0004-2803.202000000-76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/09/2020] [Indexed: 11/22/2022]
Abstract
Therapeutic drug monitoring (TDM) of infliximab (IFX) has been recognized as an important strategy in the management of secondary loss of response to this agent, guiding clinical decision-making in the management of inflammatory bowel diseases (IBD). Although most of the data on the application of TDM for IFX refer to the maintenance phase of treatment, many studies have associated higher drug concentrations, specially in the induction phase, with achievement of important treatment targets, such as clinical remission and mucosal healing. This brief communication aims to summarize the literature on the use of TDM during induction phase of IFX and propose application of a simplified approach which can be useful into clinical practice, aiming better outcomes to IBD patients.
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Agrawal M, Dubinsky MC, Colombel JF. Therapeutic Drug Monitoring of Anti-tumour Necrosis Factor Agents in Inflammatory Bowel Diseases: The Jury Is Still Out. J Crohns Colitis 2020; 14:1035-1036. [PMID: 32894298 DOI: 10.1093/ecco-jcc/jjaa092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Manasi Agrawal
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marla C Dubinsky
- Division of Pediatric Gastroenterology and Nutrition, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Cordes F, Foell D, Ding JN, Varga G, Bettenworth D. Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn's disease. World J Gastroenterol 2020; 26:4055-4075. [PMID: 32821070 PMCID: PMC7403801 DOI: 10.3748/wjg.v26.i28.4055] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/24/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
In 2018, the pan-Janus kinase (JAK) inhibitor tofacitinib was launched for the treatment of ulcerative colitis (UC). Although tofacitinib has proven efficacious in patients with active UC, it failed in patients with Crohn's disease (CD). This finding strongly hints at a different contribution of JAK signaling in both entities. Here, we review the current knowledge on the interplay between the JAK/signal transducer and activator of transcription (STAT) pathway and inflammatory bowel diseases (IBD). In particular, we provide a detailed overview of the differences and similarities of JAK/STAT-signaling in UC and CD, highlight the impact of the JAK/STAT pathway in experimental colitis models and summarize the published evidence on JAK/STAT-signaling in immune cells of IBD as well as the genetic association between the JAK/STAT pathway and IBD. Finally, we describe novel treatment strategies targeting JAK/STAT inhibition in UC and CD and comment on the limitations and challenges of the new drug class.
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Affiliation(s)
- Friederike Cordes
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - John Nik Ding
- Department of Gastroenterology, St. Vincent’s Hospital, Melbourne 3002, Australia
- Department of Medicine, University of Melbourne, East Melbourne 3002, Australia
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
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Optimizing Antitumor Necrosis Factor Treatment in Pediatric Inflammatory Bowel Disease With Therapeutic Drug Monitoring. J Pediatr Gastroenterol Nutr 2020; 71:12-18. [PMID: 32142005 DOI: 10.1097/mpg.0000000000002704] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Biological agents have revolutionized inflammatory bowel disease treatment but primary nonresponse and secondary loss of response are common with resulting adverse outcomes. Clinical trials demonstrated an association between serum drug concentrations, as well as the presence of antidrug antibodies, and loss-of-response. Therapeutic drug monitoring (TDM), defined as the evaluation of drug concentrations and antidrug antibodies, is appearing as a strategy to optimize treatment and take full advantage from these drugs. TDM appears to be a promising tool in clinical practice, especially in pediatric patients, who have pronounced fluctuations in the pharmacokinetics of the drugs.The authors present a literature review about antitumor necrosis factor therapy optimization based on personalized treatment strategies according to TDM and possible strategies to recapture loss of response, including an algorithm for practical management.
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Prediction of treatment failure during infliximab induction therapy in inflammatory bowel disease patients based on pharmacokinetic and pharmacodynamic modeling. Eur J Pharm Sci 2020; 150:105317. [PMID: 32205229 DOI: 10.1016/j.ejps.2020.105317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/27/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND In infliximab (IFX) treatment for Crohn's disease (CD) and ulcerative colitis (UC), it is difficult to predict treatment failure during the induction phase. In the present study for optimal IFX treatment, we attempted to estimate serum IFX concentration and clinical response in individual patients during the induction phase to predict the indication of therapeutic effect and the possibility of treatment failure in the maintenance phase. METHODS We estimated pharmacokinetic and pharmacodynamic (PK/PD) parameters and predicted the serum IFX concentration and clinical response using a PK/PD model and Markov chain Monte Carlo Bayesian analysis method during the induction phase. Then, we determined whether the indication of therapeutic effect between predicted and observed clinical response were matched during the maintenance phase. RESULTS Data obtained from 15 patients were analyzed. The correlation between predicted and observed values of serum IFX concentration (Pearson product-moment correlation coefficient, 0.700; P < 0.0001, n = 68) and clinical response of CD patients (0.790; P < 0.0001, n = 25) and UC patients (0.702; P = 0.0004, n = 21) were significantly high. The indication of therapeutic effect at the final time point of each patient (from day 115 to day 203) were successfully predicted in 14 of 15 patients (93.3%). CONCLUSIONS This study presents prediction of serum IFX concentration and clinical response in individual patients during induction therapy, with presumption of the indication of therapeutic effect and the treatment failure in the maintenance phase. Our results show the possibility of optimizing IFX therapy during the induction phase.
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Samaan MA, Cunningham G, Tamilarasan AG, Beltran L, Pavlidis P, Ray S, Mawdsley J, Anderson SH, Sanderson JD, Arkir Z, Irving PM. Therapeutic thresholds for golimumab serum concentrations during induction and maintenance therapy in ulcerative colitis: results from the GO-LEVEL study. Aliment Pharmacol Ther 2020; 52:292-302. [PMID: 32506695 DOI: 10.1111/apt.15808] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/13/2020] [Accepted: 05/03/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Significant associations between serum golimumab concentrations and favourable outcomes have been observed during both induction and maintenance therapy in ulcerative colitis (UC). However, data regarding optimal therapeutic serum golimumab concentration thresholds are limited. AIMS To identify optimal serum golimumab concentration thresholds during induction and maintenance treatment with golimumab. METHODS GO-LEVEL was an open label, phase IV study that included a prospective cohort of UC patients commencing golimumab, as well as a cross-sectional cohort receiving maintenance treatment. Patients commencing induction for active UC (defined as a simple clinical colitis activity index [SCCAI] >5 in addition to a raised faecal calprotectin [FC] >59μg/g or, raised C-reactive protein [CRP] [>5mg/L] or, Mayo endoscopic disease activity 2 or 3) were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare or during remission. Combined clinical-biochemical remission was defined as SCCAI ≤2 and FC <250μg/g. Serum golimumab concentrations were measured using a commercially available ELISA (LISATRACKER, Theradiag). RESULTS Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined clinical-biochemical remission at week 6. The median serum golimumab concentration of those in combined clinical-biochemical remission was significantly higher than those who were not (5.0 vs 3.1 μg/mL, respectively, P = 0.03). Receiver operating characteristic (ROC) curve analysis demonstrated 3.8 μg/mL as the optimal threshold (sensitivity 0.71, specificity 0.65, area under curve [AUC] 0.72, positive predictive value [PPV] 0.59 and negative predictive value [NPV] 0.79). Sixty-three patients were included in the maintenance cohort; 31 (49%) were in combined remission, 32 (51%) were not. The median serum golimumab concentration of those in combined remission was significantly higher (2.9 vs 2.1 μg/mL, respectively, P = 0.01). ROC curve analysis demonstrated 2.4 μg/mL as the optimal threshold (sensitivity 0.68, specificity 0.66, AUC 0.68, PPV 0.65 and NPV 0.66). CONCLUSIONS GO-LEVEL (NCT03124121) offers further evidence regarding golimumab's exposure-response relationship. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested therapeutic thresholds of 3.8 μg/mL at week 6 and 2.4 μg/mL during maintenance.
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Affiliation(s)
- Mark A Samaan
- Gastroenterology, Guy's & St Thomas' Hospital, London, UK
| | | | | | - Luisa Beltran
- Viapath Laboratories, Guy's & St Thomas' Hospital, London, UK
| | - Polychronis Pavlidis
- Gastroenterology, Guy's & St Thomas' Hospital, London, UK.,School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Shuvra Ray
- Gastroenterology, Guy's & St Thomas' Hospital, London, UK
| | - Joel Mawdsley
- Gastroenterology, Guy's & St Thomas' Hospital, London, UK
| | | | | | - Zehra Arkir
- Viapath Laboratories, Guy's & St Thomas' Hospital, London, UK
| | - Peter M Irving
- Gastroenterology, Guy's & St Thomas' Hospital, London, UK.,School of Immunology and Microbial Sciences, King's College London, London, UK
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Lyles JL, Mulgund AA, Bauman LE, Su W, Fei L, Chona DL, Sharma P, Etter RK, Hellmann J, Denson LA, Minar P, Dykes DM, Rosen MJ. Effect of a Practice-wide Anti-TNF Proactive Therapeutic Drug Monitoring Program on Outcomes in Pediatric Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2020; 27:482-492. [PMID: 32448898 PMCID: PMC7957222 DOI: 10.1093/ibd/izaa102] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Reports on the feasibility and effectiveness of translating proactive, antitumor necrosis factor (TNF) therapeutic drug monitoring (TDM) for inflammatory bowel disease into practice-wide quality improvement (QI) are lacking. We aimed to determine whether a TDM QI program improved outcomes at a large academic pediatric gastroenterology practice. METHODS We instituted local anti-TNF TDM practice guidelines to proactively monitor and optimize drug levels (goal >5 μg/mL). We conducted a retrospective single-center cohort analysis of patient outcomes before (pre-TDM) and after (post-TDM) guideline institution and assessed the independent effect by multivariable regression. Primary outcome was sustained clinical remission (SCR22-52), defined as physician global assessment (PGA) of inactive from 22 to 52 weeks and off corticosteroids at 52 weeks. RESULTS We identified 108 pre-TDM and 206 post-TDM patients. The SCR22-52 was achieved in 42% of pre-TDM and 59% of post-TDM patients (risk difference, 17.6%; 95% CI, 5.4-29%; P = 0.004). The post-TDM group had an increased adjusted odds of achieving SCR22-52 (odds ratio, 2.03; 95% CI, 1.27-3.26; P = 0.003). The adjusted risk of developing high titer antidrug antibodies (ADAs) was lower in the post-TDM group (hazard ratio, 0.18; 95% CI, 0.09-0.35; P < 0.001). Although the risk of anti-TNF cessation for any reason was not significantly different, there was a lower adjusted risk of cessation related to any detectable ADA in the post-TDM group (hazard ratio, 0.45; 95% CI, 0.26-0.77; P = 0.003). CONCLUSIONS A practice-wide proactive anti-TNF TDM QI program improved key clinical outcomes at our institution, including sustained clinical remission, incidence of high titer ADA, and anti-TNF cessation related to ADA.
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Affiliation(s)
- John L Lyles
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Aditi A Mulgund
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA,Division of Gastroenterology and Hepatology, Medical College of Wisconsin Associated Hospitals, Milwaukee, WI, USA
| | - Laura E Bauman
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Weizhe Su
- Division of Statistics and Data Science, Department of Mathematical Sciences, University of Cincinnati, Cincinnati, OH, USA
| | - Lin Fei
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Deepika L Chona
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Puneet Sharma
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Renee K Etter
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Jennifer Hellmann
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lee A Denson
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Phillip Minar
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Dana M Dykes
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,GI Care for Kids, Atlanta, GA, USA
| | - Michael J Rosen
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA,Address correspondence to: Michael J. Rosen MD, MSCI, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 2010, Cincinnati, OH, 45229, USA. E-mail:
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Gil Candel M, Gascón Cánovas JJ, Urbieta Sanz E, Gómez Espín R, Nicolás de Prado I, Iniesta Navalón C. Usefulness of therapeutic drug monitoring of infliximab during the induction period in patients with inflammatory bowel disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 112:360-366. [PMID: 32338010 DOI: 10.17235/reed.2020.6618/2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
INTRODUCTION previous studies have shown that higher infliximab trough levels are associated with favorable short-term and long-term therapeutic outcomes in inflammatory bowel disease. There is a need to determine which patients could benefit from proactive therapeutic drug monitoring in the induction phase. The aim of this study was to evaluate the pharmacokinetic variability of infliximab, determine the factors associated with achieving target infliximab trough levels in the induction phase and analyze the clinical and biochemical response at week 26 of treatment. PATIENTS AND METHODS a retrospective observational study was performed of patients with inflammatory bowel disease and data available on serum levels of infliximab during the induction period. The percentage of patients that achieved target infliximab trough levels at week 6 was determined. Clinical remission and response and biochemical remission were evaluated at week 26. RESULTS thirty patients were included and only 13 (43.3 %) had infliximab trough levels > 15 µg/mL at week 6. A clinical response was observed during the maintenance period in 71.4 % of patients, their infliximab levels were significantly higher than in non-responders (6.3 µg/mL [IQR: 6.7] vs 1.0 µg/mL [IQR: 5.0], respectively; p = 0.016). Likewise, 53.6 % of patients achieved biochemical remission (responders 6.2 µg/mL [IQR: 5.2] vs non-responders 3.2 µg/mL [IQR: 5.0]; p = 0.031). CONCLUSION less than half of patients had target infliximab levels during the induction period. Therapeutic drug monitoring during this period is related to the achievement of therapeutic levels of infliximab and may lead to a better clinical response in these patients.
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Affiliation(s)
- Mayte Gil Candel
- Hospital Pharmacy, Hospital General Universitario Reina Sofía, España
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Ding X, Zhu R, Wu J, Xue L, Gu M, Miao L. Early Adalimumab and Anti-Adalimumab Antibody Levels for Prediction of Primary Nonresponse in Ankylosing Spondylitis Patients. Clin Transl Sci 2020; 13:547-554. [PMID: 31961477 PMCID: PMC7214645 DOI: 10.1111/cts.12738] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 11/02/2019] [Indexed: 12/11/2022] Open
Abstract
This study aimed at exploring the concentration‐effect relationship of adalimumab and early adalimumab and anti‐adalimumab antibody (AAA) levels in predicting primary nonresponse in a real‐world pilot cohort of patients with ankylosing spondylitis. Thirty‐one patients were included. The Ankylosing Spondylitis Disease Activity Score improved with increasing adalimumab trough level at week 12 and reached a major improvement with levels between 8 and 12 μg/mL. Moreover, weeks 4 and 2 adalimumab levels below 4.28 and 3.37 μg/mL were predictive of primary nonresponse (area under the curve (AUC) = 0.89, 0.88; P = 0.0003, P = 0.034, respectively). Week 4 AAA signal‐to‐noise levels were significantly higher among primary nonresponders, and the cutoff for primary nonresponse prediction was above 5.31 (AUC = 0.81; P = 0.004). Adalimumab trough levels in a range of 8–12 μg/mL are optimum to reach major improvement, and lower adalimumab with higher AAA levels at the early stage (week 4) predict primary nonresponse by supporting proactive monitoring to optimize adalimumab therapy.
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Affiliation(s)
- Xiaoliang Ding
- Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Ruifang Zhu
- Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Jian Wu
- Department of Rheumatology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ling Xue
- Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Meihua Gu
- Department of Rheumatology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Liyan Miao
- Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
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Abstract
The landscape of pediatric inflammatory bowel disease is rapidly evolving. The therapeutic advances seen in the adult arena are rapidly being adopted by pediatric gastroenterologists and evaluated in both controlled trials and real-world experience. Though anti-tumor necrosis factor agents have been the primary therapy over the last decade, recently there has been an expansion of therapeutic targets and alternative mechanism of action drugs with a focus on individualized and personalized therapy. By reviewing epidemiology, pathophysiology, and goals of treatment, we hope to frame the discussion of current and novel therapeutics for the pediatric gastroenterologist. As scientific discovery continues to push the envelope in defining our understanding of pediatric inflammatory bowel disease, the current era of therapeutics gives us hope that a cure may be realized soon.
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Affiliation(s)
- Bhaskar Gurram
- University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ashish S. Patel
- University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
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Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee B, Lomer MCE, Parkes GC, Selinger C, Barrett KJ, Davies RJ, Bennett C, Gittens S, Dunlop MG, Faiz O, Fraser A, Garrick V, Johnston PD, Parkes M, Sanderson J, Terry H, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen R, Hawthorne AB. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019; 68:s1-s106. [PMID: 31562236 PMCID: PMC6872448 DOI: 10.1136/gutjnl-2019-318484] [Citation(s) in RCA: 1512] [Impact Index Per Article: 252.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/10/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
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Affiliation(s)
- Christopher Andrew Lamb
- Newcastle University, Newcastle upon Tyne, UK
- Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Nicholas A Kennedy
- Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
- University of Exeter, Exeter, UK
| | - Tim Raine
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
| | - Philip Anthony Hendy
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
- Imperial College London, London, UK
| | - Philip J Smith
- Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
| | - Jimmy K Limdi
- The Pennine Acute Hospitals NHS Trust, Manchester, UK
- University of Manchester, Manchester, UK
| | - Bu'Hussain Hayee
- King's College Hospital NHS Foundation Trust, London, UK
- King's College London, London, UK
| | - Miranda C E Lomer
- King's College London, London, UK
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Gareth C Parkes
- Barts Health NHS Trust, London, UK
- Barts and the London School of Medicine and Dentistry, London, UK
| | - Christian Selinger
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
- University of Leeds, Leeds, UK
| | | | - R Justin Davies
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
- University of Cambridge, Cambridge, UK
| | - Cathy Bennett
- Systematic Research Ltd, Quorn, UK
- Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | | | - Malcolm G Dunlop
- University of Edinburgh, Edinburgh, UK
- Western General Hospital, Edinburgh, UK
| | - Omar Faiz
- Imperial College London, London, UK
- St Mark's Hospital, Harrow, UK
| | - Aileen Fraser
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | | | | | - Miles Parkes
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
| | - Jeremy Sanderson
- King's College London, London, UK
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - Daniel R Gaya
- Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| | - Tariq H Iqbal
- Queen Elizabeth Hospital Birmingham NHSFoundation Trust, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - Stuart A Taylor
- University College London, London, UK
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Melissa Smith
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
- Brighton and Sussex Medical School, Brighton, UK
| | - Matthew Brookes
- Royal Wolverhampton NHS Trust, Wolverhampton, UK
- University of Wolverhampton, Wolverhampton, UK
| | - Richard Hansen
- Royal Hospital for Children Glasgow, Glasgow, UK
- University of Glasgow, Glasgow, UK
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Abstract
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
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45
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Martins CDA, Moss AC, Sobrado CW, Queiroz NSF. Practical Aspects of Proactive TDM for Anti-TNF Agents in IBD: Defining Time Points and Thresholds to Target. CROHNS & COLITIS 360 2019. [DOI: 10.1093/crocol/otz049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Abstract
Serum biologic drug concentrations have been associated with favorable therapeutic outcomes in inflammatory bowel diseases, while low or undetectable drug levels have been linked to immunogenicity and treatment failure. Therapeutic drug monitoring (TDM) in the context of clinical relapse can guide decision making and is supported by professional groups. Proactive TDM consists of measurement of trough concentration with the goal of optimizing drug concentration in patients with clinical response/remission. Recent findings suggest that this approach can improve the efficacy of antitumor necrosis factor agents (anti-TNF). In this article, we summarize the rationale for proactive TDM for anti-TNF agents in practice, identify limitations in this evidence base, and provide practical advice for use in the clinic.
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Affiliation(s)
- Camilla de Almeida Martins
- Department of Gastroenterology and Division of Colorectal Surgery, University of Sao Paulo School of Medicine, São Paulo, Brazil
| | - Alan C Moss
- Director of Crohn’s & Colitis Program, Boston Medical Center, Boston, MA
| | - Carlos Walter Sobrado
- Department of Gastroenterology and Division of Colorectal Surgery, University of Sao Paulo School of Medicine, São Paulo, Brazil
| | - Natália Sousa Freitas Queiroz
- Department of Gastroenterology and Division of Colorectal Surgery, University of Sao Paulo School of Medicine, São Paulo, Brazil
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46
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Antonelli E, Torti G, Bassotti G. Inhibitors of the Janus Kinases: A New Oral Treatment Option for Ulcerative Colitis. J Clin Gastroenterol 2019; 53:635-640. [PMID: 31373941 DOI: 10.1097/mcg.0000000000001250] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The treatment of ulcerative colitis (UC) is based on conventional therapies (aminosalicylates, corticosteroids, and immunosuppressants) and when these are ineffective, biologic drugs. However, in a substantial portion of patients undergoing treatment with biologic agents there is primary or secondary loss of response. Thus, new therapeutic options are been actively explored; among these, there is interest in the Janus kinase (JAK) inhibitors, small molecules that can be administered orally. METHODS We carried out an extensive literature search concerning the effects of JAK inhibitors for the treatment of patients with UC. RESULTS Tofacitinib is the drug more extensively studied in this setting, and it was recently approved in Europe for the treatment of moderate to severe UC. The available data suggest that this drug can be effective in obtaining clinical and endoscopic remission in UC patients unresponsive to other treatments, even in those previously treated with biologic drugs. In addition, the drug was able to improve significantly the quality of life of these patients. There are still few data available for the treatment of UC with other JAK inhibitors. CONCLUSIONS The JAK inhibitors, in particular tofacitinib, are a new class of orally administered drugs effective for the treatment of UC. However, more studies are needed to ascertain the safety of tofacitinib in the long term and whether other compounds of this class may be equally effective.
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Affiliation(s)
| | - Gabriele Torti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy
| | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy
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47
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Shah NB, Jolly JA, Horst SN, Peter M, Limper H, Zuckerman AD. Development of quality measures for use of self-injectable biologic therapy in inflammatory bowel disease: An integrated specialty pharmacy initiative. Am J Health Syst Pharm 2019; 76:1296-1304. [PMID: 31418790 DOI: 10.1093/ajhp/zxz142] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
PURPOSE The development of a tool to measure medication safety, therapeutic efficacy, and other quality outcomes in patients receiving self-injectable biologic therapy for the management of inflammatory bowel disease (IBD) at a health-system specialty pharmacy is described. SUMMARY Through a collaborative initiative by pharmacists, gastro-enterologists, and representatives of a pharmacy benefit manager and a pharmaceutical company, a set of clinical and specialty pharmacy quality measures was developed. The clinical measures are intended for use in assessing patient safety, disease status, treatment efficacy, and healthcare resource utilization during 3 assessments (pre-treatment, on-treatment, and longitudinal). The specialty pharmacy measures can be used to assess medication adherence, medication persistence, specialty pharmacy accreditation, and patient satisfaction. The proposed quality measures provide a foundation for evaluating the quality of IBD care and improving patient outcomes within a health-system specialty pharmacy. Future efforts to validate and implement the tool in clinical practice are planned. CONCLUSION The proposed quality measures provide a foundation for future inquiry regarding the appropriateness and feasibility of integrating the measures into clinical care. Further work is needed to implement and validate these quality measures and determine their impact in optimizing health outcomes.
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Affiliation(s)
- Nisha B Shah
- Vanderbilt Specialty Pharmacy, Vanderbilt University Medical Center, Nashville, TN
| | - Jacob A Jolly
- Vanderbilt Specialty Pharmacy, Vanderbilt University Medical Center, Nashville, TN
| | - Sara N Horst
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN
| | - Megan Peter
- Vanderbilt Specialty Pharmacy, Vanderbilt University Medical Center, Nashville, TN
| | - Heather Limper
- General Internal Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN
| | - Autumn D Zuckerman
- Vanderbilt Specialty Pharmacy, Vanderbilt University Medical Center, Nashville, TN
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48
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Papamichael K, Vogelzang EH, Lambert J, Wolbink G, Cheifetz AS. Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases. Expert Rev Clin Immunol 2019; 15:837-848. [PMID: 31180729 DOI: 10.1080/1744666x.2019.1630273] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 06/07/2019] [Indexed: 12/22/2022]
Abstract
Introduction: Biologic therapy has revolutionized the treatment of immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid and psoriatic arthritis, ankylosing spondylitis and psoriasis. Nevertheless, some patients exhibit primary nonresponse (PNR) or secondary loss of response (SLR) to biologics. Areas covered: This collaborative review provides data on the role of therapeutic drug monitoring (TDM) in IMID for optimizing biologic therapy including infliximab, adalimumab, certolizumab pegol etanercept and golimumab vedolizumab, secukinumab and ustekinumab. Expert opinion: Most exposure-response relationship studies show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IMID with higher drug concentrations typically associated with more objective outcomes. Clinically, reactive TDM rationalizes the management of PNR and SLR to anti-tumor necrosis factor therapy and is emerging as the new standard of care in IBD as it is also more cost-effective than empiric dose escalation. Preliminary data suggest that proactive TDM with the goal to achieve a threshold drug concentration is associated with better therapeutic outcomes when compared to empiric drug optimization and/or reactive TDM of infliximab and adalimumab in IBD. However, more data from well-designed prospective studies are needed to prove the benefit of TDM-based algorithms in real life clinical practice in IMID.
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Affiliation(s)
- Konstantinos Papamichael
- a Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
| | - Erik H Vogelzang
- b Rheumatology and Immunology Center, Research by AMC, READE and VUMC , Amsterdam , the Netherlands
| | - Jo Lambert
- c Department of Dermatology, Ghent University , Ghent , Belgium
| | - Gertjan Wolbink
- b Rheumatology and Immunology Center, Research by AMC, READE and VUMC , Amsterdam , the Netherlands
- d Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Center , Amsterdam , the Netherlands
| | - Adam S Cheifetz
- a Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
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Wang MH, Friton JJ, Raffals LE, Leighton JA, Pasha SF, Picco MF, Cushing KC, Monroe K, Nix BD, Newberry RD, Faubion WA. Novel Genetic Risk Variants Can Predict Anti-TNF Agent Response in Patients With Inflammatory Bowel Disease. J Crohns Colitis 2019; 13:1036-1043. [PMID: 30689765 PMCID: PMC7185197 DOI: 10.1093/ecco-jcc/jjz017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/16/2018] [Accepted: 01/20/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND It is important to identify patients with inflammatory bowel disease [IBD] refractory to anti-tumour necrosis factor [TNF] therapy, to avoid potential adverse effects and to adopt different treatment strategies. We aimed to identify and validate clinical and genetic factors to predict anti-TNF response in patients with IBD. MATERIALS AND METHODS Mayo Clinic and Washington University IBD genetic association study cohorts were used as discovery and replicate datasets, respectively. Clinical factors included sex, age at diagnosis, disease duration and phenotype, disease location, bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy. RESULTS Of 474 patients with IBD treated with anti-TNF therapy, 41 [8.7%] were refractory to therapy and 433 [91.3%] had response. Multivariate analysis showed history of immunomodulator use (odds ratio 10.2, p = 8.73E-4) and bowel resection (odds ratio 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents. Among genetic loci, two [rs116724455 in TNFSF4/18, rs2228416 in PLIN2] were successfully replicated and another four [rs762787, rs9572250, rs144256942, rs523781] with suggestive evidence were found. An exploratory risk model predictability [area under the curve] increased from 0.72 [clinical predictors] to 0.89 after adding genetic predictors. Through identified clinical and genetic predictors, we constructed a preliminary anti-TNF refractory score to differentiate anti-TNF non-responders (mean [standard deviation] score, 5.49 [0.99]) from responders (2.65 [0.39]; p = 4.33E-23). CONCLUSIONS Novel and validated genetic loci, including variants in TNFSF, were found associated with anti-TNF response in patients with IBD. Future validation of the exploratory risk model in a large prospective cohort is warranted.
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Affiliation(s)
- Ming-Hsi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA,Corresponding author: Ming-Hsi Wang, MD, PhD, Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA. Tel.: 904-953-6970; fax: 904-953-6225;
| | - Jessica J Friton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jonathan A Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Shabana F Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Michael F Picco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Kelly C Cushing
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA,Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - Kelly Monroe
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - Billy D Nix
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - Rodney D Newberry
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MI, USA
| | - William A Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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50
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Papamichael K, Cheifetz AS, Melmed GY, Irving PM, Vande Casteele N, Kozuch PL, Raffals LE, Baidoo L, Bressler B, Devlin SM, Jones J, Kaplan GG, Sparrow MP, Velayos FS, Ullman T, Siegel CA. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2019; 17:1655-1668.e3. [PMID: 30928454 PMCID: PMC6661210 DOI: 10.1016/j.cgh.2019.03.037] [Citation(s) in RCA: 236] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/24/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.
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Affiliation(s)
| | - Adam S Cheifetz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | - Gil Y Melmed
- Cedars-Sinai Medical Center, Los Angeles, California
| | | | | | | | | | - Leonard Baidoo
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | | | | | | | | | | | | | - Thomas Ullman
- Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York
| | - Corey A Siegel
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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