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Westhovens R, Wiland P, Zawadzki M, Ivanova D, Kasay AB, El-Khouri EC, Balázs É, Shevchuk S, Eliseeva L, Stanislavchuk M, Yatsyshyn R, Hrycaj P, Jaworski J, Zhdan V, Trefler J, Shesternya P, Lee SJ, Kim SH, Suh JH, Lee SG, Han NR, Yoo DH. Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial. Rheumatology (Oxford) 2021; 60:2277-2287. [PMID: 33230526 PMCID: PMC8121438 DOI: 10.1093/rheumatology/keaa580] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/22/2020] [Indexed: 12/16/2022] Open
Abstract
Objective To assess non-inferiority of s.c. to i.v. CT-P13 in RA. Methods Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46–54) then PFS (W56–64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: −0.6). Results Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS. Conclusion CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03147248.
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Affiliation(s)
- Rene Westhovens
- Skeletal Biology and Engineering Research Center KU Leuven, Rheumatology University Hospital Leuven, Leuven, Belgium
| | | | | | - Delina Ivanova
- Diagnostic and Consulting Center Aleksandrovska, Sofia, Bulgaria
| | | | | | - Éva Balázs
- Csongrád Megyei Dr. Bugyi István Kórház, Szentes, Hungary
| | - Sergii Shevchuk
- National Pirogov Memorial Medical University, Vinnytsia, Ukraine
| | | | | | - Roman Yatsyshyn
- Ivano-Frankivsk Regional Clinical Hospital, Ivano-Frankivsk, Ukraine
| | | | | | - Vyacheslav Zhdan
- Poltava Regional Clinical Hospital n.a. M.V. Sklifosovskyi, Poltava, Ukraine
| | | | | | | | | | | | | | - Noo Ri Han
- Celltrion, Inc., Incheon, Republic of Korea
| | - Dae Hyun Yoo
- Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
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Ehrenpreis ED. Pharmacokinetic Effects of Antidrug Antibodies Occurring in Healthy Subjects After a Single Dose of Intravenous Infliximab. Drugs R D 2017; 17:607-613. [PMID: 28879645 PMCID: PMC5694424 DOI: 10.1007/s40268-017-0211-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Infliximab pharmacokinetic studies have been performed in patients receiving chronic infliximab therapy. In these patients, infliximab antidrug antibodies (ADAs) increase infliximab clearance and decrease serum levels and drug efficacy. OBJECTIVE This study analyzed the pharmacokinetic effect of infliximab ADAs in healthy subjects receiving a single dose of intravenous infliximab. METHODS Data were obtained from a single-blind, parallel-group, single-dose study of healthy subjects receiving 5 mg/kg of intravenous SB2 (infliximab biosimilar), EU-sourced Remicade (EU-IFX) or US-sourced Remicade (US-IFX). Serum infliximab was measured at 1, 2, 3, 6, 12, 24, 48, and 72 h and at 5, 7, 14, 21, 28, 42, 56, and 70 days after administration. ADAs were measured pre-dose and at 29 and 71 days. Data from the first ten subjects randomized to each treatment arm were utilized for this study. A two-compartment model of the serum infliximab vs. time curve was developed using nonlinear regression. RESULTS At 10 weeks, 11 subjects (37%) developed ADAs. ADAs were detected in four subjects after SB2, one subject after EU-IFX, and six subjects after US-IFX infusion. Of these, neutralizing antibodies occurred in one subject after SB2, in no subjects after EU-IFX, and in three subjects after US-IFX infusion. Infliximab clearance was increased in subjects with ADAs vs. those without ADAs (12.89 ± 2.69 vs. 9.90 ± 1.74 ml/h; p < 0.0005). The elimination half-time was shorter in subjects with ADAs (282.4 ± 56.4 vs. 343.3 ± 61.9 h; p < 0.01). Serum infliximab measured at 8 weeks correlated closely with infliximab clearance (R 2 = 0.5494; p < 0.0001). CONCLUSION ADAs are common in healthy subjects after a single intravenous dose of infliximab and result in faster infliximab clearance, shorter elimination time, and lower serum infliximab levels. These data confirm that ADAs are common with biologic therapy and significantly impact the efficacy of these drugs.
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Plasencia C, Jurado T, Villalba A, Peitedado D, Casla MTL, Nuño L, Bonilla MG, Martínez-Feito A, Martín-Mola E, Pascual-Salcedo D, Balsa A. Effect of Infliximab Dose Increase in Rheumatoid Arthritis at Different Trough Concentrations: A Cohort Study in Clinical Practice Conditions. Front Med (Lausanne) 2015; 2:71. [PMID: 26501060 PMCID: PMC4597116 DOI: 10.3389/fmed.2015.00071] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 09/17/2015] [Indexed: 11/13/2022] Open
Abstract
Background Evidence supporting treatment intensification in rheumatoid arthritis (RA) is limited and controversial. We explored outcomes of infliximab dose increases and accounted for pre-existing trough levels in patients with active RA. Methods This study was a retrospective study of 42 RA patients who received increased infliximab following an insufficient response (DAS28 >3.2). Serum concentrations of infliximab and antibodies to infliximab (ATI) and DAS28 and EULAR clinical response parameters were recorded for 1 year. Analyses were performed in three patient groups that were defined by infliximab serum concentration prior to treatment enhancement: no detectable, low (<1.1 μg/mL) or high (≥1.1 μg/mL) drug levels. Results No circulating infliximab was detected in 20 patients (47.6%), but 13 (31%) and 9 (21.4%) patients exhibited low and high levels, respectively. ATI was only detected in patients with no detectable drug levels because the drug interferes with ELISA. DAS28 disease activity globally showed a modest improvement after dose escalation, but this improvement did not persist after 6 and 12 months. Infliximab serum levels increased significantly in the high group (p = 0.016), but no increase was achieved in the low and no detectable groups. The three study groups exhibited similar disease activity over time, and no improvement was observed in the non-responder EULAR rates. Conclusion These results suggest that the efficacy of an infliximab dose increase is limited, and the response is independent of the infliximab trough serum concentration that is achieved prior to escalation.
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Affiliation(s)
- Chamaida Plasencia
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Teresa Jurado
- Immunology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Alejandro Villalba
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Diana Peitedado
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Maria Teresa López Casla
- Immunology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Laura Nuño
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - María Gema Bonilla
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Ana Martínez-Feito
- Immunology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Emilio Martín-Mola
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Dora Pascual-Salcedo
- Immunology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
| | - Alejandro Balsa
- Rheumatology Unit, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid , Spain
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Ternant D, Ducourau E, Fuzibet P, Vignault C, Watier H, Lequerré T, Le Loët X, Vittecoq O, Goupille P, Mulleman D, Paintaud G. Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis. Br J Clin Pharmacol 2015; 79:286-97. [PMID: 25223394 DOI: 10.1111/bcp.12509] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 09/06/2014] [Indexed: 12/12/2022] Open
Abstract
AIMS This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokinetic-pharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA). METHODS Adalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated. RESULTS Thirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd /F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day(-1) (17%); first-order absorption rate (ka ) = 0.28 day(-1) ; CRP input (kin ) = 22.0 mg l(-1) day(-1) (65%); adalimumab concentration leading to a 50% decrease in kin (C50 ) = 3.6 mg l(-1) (88%); baseline DAS28 (DAS0 ) = 5.5 mg l(-1) (11%); and adalimumab concentration leading to 50% decrease of DAS0 (IC50 ) = 11.0 mg l(-1) (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection. CONCLUSIONS This is the first study to describe adalimumab pharmacokinetics and the concentration-effect relationship in RA. A 160 mg loading dose may lead to an increased benefit from treatment in RA patients.
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Affiliation(s)
- David Ternant
- CNRS, UMR 7292, 'Genetics, Immunotherapy, Chemistry and Cancer', Université François Rabelais de Tours, Tours, France; Laboratoire de pharmacologie-toxicologie, CHRU de Tours, Tours, France
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Emery P, Sebba A, Huizinga TWJ. Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis. Ann Rheum Dis 2013; 72:1897-904. [PMID: 23918035 PMCID: PMC3841743 DOI: 10.1136/annrheumdis-2013-203485] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 06/20/2013] [Accepted: 07/09/2013] [Indexed: 12/17/2022]
Abstract
Clinical evidence demonstrates coadministration of tumour necrosis factor inhibitor (TNFi) agents and methotrexate (MTX) is more efficacious than administration of TNFi agents alone in patients with rheumatoid arthritis, leading to the perception that coadministration of MTX with all biologic agents or oral disease-modifying antirheumatic drugs is necessary for maximum efficacy. Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy. Additionally, an analysis of healthcare claims data showed that when MTX was prescribed in conjunction with a biologic agent, as many as 58% of patients did not collect the MTX prescription. Given this discrepancy between perception and real life, we conducted a review of the peer-reviewed literature and rheumatology medical congress abstracts to determine whether data support biologic monotherapy as a treatment option for patients with rheumatoid arthritis. Our analysis suggests only for tocilizumab is there evidence that the efficacy of biologic monotherapy is comparable with combination therapy with MTX.
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Affiliation(s)
- Paul Emery
- Leeds Institute of Rheumatic & Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust United Kingdom, Leeds, UK
| | - Anthony Sebba
- Department of Rheumatology, University of South Florida, Tampa, Florida, USA
| | - Tom W J Huizinga
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
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Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P, Mikazane H, Gutierrez-Ureña S, Lim M, Lee YA, Lee SJ, Kim H, Yoo DH, Braun J. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013; 72:1605-12. [PMID: 23687259 PMCID: PMC3786643 DOI: 10.1136/annrheumdis-2012-203091] [Citation(s) in RCA: 457] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS). METHODS Phase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (Cmax,ss) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed. RESULTS Geometric mean AUC was 32 765.8 μgh/ml for CT-P13 and 31 359.3 μgh/ml for INX. Geometric mean Cmax,ss was 147.0 μg/ml for CT-P13 and 144.8 μg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for Cmax,ss. ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively. CONCLUSIONS The PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30.
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Affiliation(s)
- Won Park
- Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea.
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McConnell J, Parvulescu-Codrea S, Behm B, Hill B, Dunkle E, Finke K, Snyder K, Tuskey A, Cox D, Woodward B. Accelerated infliximab infusions for inflammatory bowel disease improve effectiveness. World J Gastrointest Pharmacol Ther 2012; 3:74-82. [PMID: 23515325 PMCID: PMC3602441 DOI: 10.4292/wjgpt.v3.i5.74] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 08/24/2012] [Accepted: 08/25/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the safety and effectiveness associated with accelerated infliximab infusion protocols in patients with inflammatory bowel disease (IBD).
METHODS: Original protocols and infusion rates were developed for the administration of infliximab over 90-min and 60-min. Then the IBD patients on stable maintenance infliximab therapy were offered accelerated infusions. To be eligible for the study, patients needed a minimum of four prior infusions. An initial infusion of 90-min was given to each patient; those tolerating the accelerated infusion were transitioned to a 60-min infusion protocol at their next and all subsequent visits. Any patient having significant infusion reactions would be reverted to the standard 120-min protocol. A change in a patient’s dose mandated a single 120-min infusion before accelerated infusions could be administered again.
RESULTS: The University of Virginia Medical Center's Institutional Review Board approved this study. Fifty IBD patients treated with infliximab 5 mg/kg, 7.5 mg/kg and 10 mg/kg were offered accelerated infusions. Forty-six patients consented to participate in the study. Nineteen (41.3%) were female, five (10.9%) were African American and nine (19.6%) had ulcerative colitis. The mean age was 42.6 years old. Patients under age 18 were excluded. Ten patients used immunosuppressive drugs concurrently out of which six were taking azathioprine, three were taking 6-mercaptopurine and one was taking methotrexate. One of the 46 study patients used corticosteroid therapy for his IBD. Seventeen of the patients used prophylactic medications prior to receiving infusions; six patients received corticosteroids as pre-medication. Four patients had a history of distant transfusion reactions to infliximab. These reactions included shortness of breath, chest tightness, flushing, pruritus and urticaria. These patients all took prophylactic medications before receiving infusions. 46 patients (27 males and 19 females) received a total of fifty 90-min infusions and ninety-three 60-min infusions. No infusion reactions were reported. There were no adverse events, including drug-related infections. None of the patients developed cancer of any type during the study timeframe. Total cost savings for administration of the both 90-min and 60-min accelerated infusions compared to standard 120-min infusions was estimated to be $53 632 ($116 965 vs $63 333, P = 0.001). One hundred and eighteen hours were saved in the administration of the accelerated infusions (17 160 min vs 10 080 min, P = 0.001). In the study population, overweight females [body mass index (BMI) > 25.00 kg/m2] were found to have statistically higher BMIs than overweight males (mean BMI 35.07 ± 2.66 kg/m2vs 30.08 ± 0.99 kg/m2, P = 0.05), finding which is of significance since obesity was described as being one of the risk factors for Crohn’s disease.
CONCLUSION: We are the first US group to report substantial cost savings, increased safety and patient satisfaction associated with accelerated infliximab infusion.
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Affiliation(s)
- John McConnell
- John McConnell, Simona Parvulescu-Codrea, Brian Behm, Beth Hill, Elizabeth Dunkle, Karen Finke, Kathryn Snyder, Anne Tuskey, Debbie Cox, Beth Woodward, Digestive Health Center of Excellence, University of Virginia Medical Center, Brookline College, Charlottesville, VA 22908, United States
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Ternant D, Mulleman D, Lauféron F, Vignault C, Ducourau E, Wendling D, Goupille P, Paintaud G. Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis. Br J Clin Pharmacol 2012; 73:55-65. [PMID: 21692827 DOI: 10.1111/j.1365-2125.2011.04050.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
AIMS Infliximab, an anti-tumour necrosis factor α monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases. The objective was to assess the influence of methotrexate on the variability of infliximab pharmacokinetics and concentration-effect relationship in axial ankylosing spondylitis (AAS) patients. METHODS Twenty-six patients with AAS were included in a prospective study. They were treated by infliximab 5 mg kg⁻¹ infusions at weeks 0, 2, 6, 12 and 18. Infliximab concentrations were measured before, and 2 and 4 h after each infusion, and at each intermediate visit (weeks 1, 3, 4, 5, 8, 10 and 14). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at each visit. Infliximab pharmacokinetics was described using a two-compartment model with first-order distribution and elimination constants. A population approach was used. Infliximab pharmacodynamics was described using the area under the BASDAI curve. RESULTS A total of 507 blood samples and 329 BASDAI measurements were collected. The following pharmacokinetic parameters were obtained (interindividual coefficient of variation): volumes of distribution for the central compartment = 2.4 l (9.6%) and peripheral compartment = 1.8 l (26%), systemic clearance = 0.23 l day⁻¹ (22%) and intercompartment clearance = 2.3 l day⁻¹. Methotrexate influenced neither pharmacokinetic nor BASDAI variability. CONCLUSIONS Using the present dosage, the clinical efficacy of infliximab is only weakly influenced by its serum concentrations. The results do not support the combination of methotrexate with infliximab in ankylosing spondylitis.
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Affiliation(s)
- David Ternant
- Université François Rabelais de Tours, Tours, France.
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Mori S. Additional use of tacrolimus after switching to tocilizumab therapy in patients with primary lack of efficacy of infliximab therapy for rheumatoid arthritis. Mod Rheumatol 2012; 22:947-50. [PMID: 22350573 DOI: 10.1007/s10165-012-0593-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 01/05/2012] [Indexed: 11/28/2022]
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Primary lack of efficacy of infliximab therapy for rheumatoid arthritis: pharmacokinetic characterization and assessment of switching to tocilizumab. Mod Rheumatol 2011; 21:628-36. [PMID: 21533855 PMCID: PMC3236821 DOI: 10.1007/s10165-011-0460-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 04/13/2011] [Indexed: 11/21/2022]
Abstract
To characterize primary failure to infliximab and determine the efficacy of switching to tocilizumab in patients with rheumatoid arthritis (RA), we examined 24 RA patients who had started on infliximab therapy (3 mg/kg) as their first biological agent. Nine of the 24 patients were found to be primary nonresponders, defined as patients who had never achieved a 20% clinical improvement according to the American College of Rheumatology criteria (ACR20) during induction therapy. The remaining 15 patients had achieved an ACR20 response to infliximab, without any relapses, for at least the first 14 weeks. A higher baseline health assessment questionnaire score was markedly associated with primary unresponsiveness to infliximab (p = 0.0005). Six of the 9 primary nonresponders showed rapid clearance of infliximab: their trough concentrations of infliximab were under 1 μg/ml. The other 3 were classified as exhibiting the residual type of unresponsiveness, which was defined as unresponsiveness in patients who maintained serum infliximab levels above 1 μg/ml. Human antichimeric antibody was not detected in the rapid-clearance nonresponders. Dose escalation (5 mg/kg) was insufficiently effective. Primary nonresponders to infliximab were started on tocilizumab therapy (8 mg/kg, every 4 weeks), and their responses were assessed after 24 weeks of this second attempt at therapy. All the nonresponders, except for a single rapid-clearance patient, had achieved an ACR20 clinical improvement at the time of assessment. In conclusion, primary nonresponders to infliximab can be classified into rapid-clearance and residual types, based on their trough concentrations of infliximab, but both types of nonresponders seem to benefit from an early decision to discontinue infliximab therapy and switch to tocilizumab.
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Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 2010; 49:493-507. [PMID: 20608753 DOI: 10.2165/11531280-000000000-00000] [Citation(s) in RCA: 528] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
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Affiliation(s)
- Ron J Keizer
- Department of Pharmacy and Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands.
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Mulleman D, Méric JC, Paintaud G, Ducourau E, Magdelaine-Beuzelin C, Valat JP, Goupille P. Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis. Arthritis Res Ther 2009; 11:R178. [PMID: 19939280 PMCID: PMC3003525 DOI: 10.1186/ar2867] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Revised: 11/17/2009] [Accepted: 11/25/2009] [Indexed: 11/17/2022] Open
Abstract
Introduction Adjustment of infliximab dosage for individuals may be useful in improving therapeutic response in rheumatoid arthritis (RA). Herein, we aimed to determine whether measurement of infliximab serum concentration modifies the therapeutic decision and improves the control of disease activity. Methods RA patients routinely treated with infliximab were included in an observational open-label study. On visit 1 (V1), according to the disease activity, a preliminary therapeutic decision was selected among four therapeutic options and a blood sample was collected to measure trough serum infliximab concentration. The final therapeutic decision, based on both disease activity and serum infliximab concentration assessed at V1, was applied at the following infusion (V2). Clinical and biological evaluations were performed at V3 and V4 and compared with those at V1. Results We included 24 patients. The final therapeutic decision differed from the preliminary decision for 12 patients (50%). For patients with increased infliximab dosage at V2, mean disease activity score for 28 joints (DAS28) decreased by about 20% at V3 or V4 as compared with V1 (P < 0.05). Decreased DAS28 was correlated with increased serum infliximab concentration (P < 0.02). Conclusions The measurement of infliximab trough concentration modifies the therapeutic decision for RA patients and helps improve control of disease activity. Therapeutic drug monitoring of infliximab in RA may be useful for individual dosage adjustment.
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Affiliation(s)
- Denis Mulleman
- Université François-Rabelais de Tours, 3 rue des Tanneurs, 37041 Tours Cedex 1, France.
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Sadowski DC, Bernstein CN, Bitton A, Croitoru K, Fedorak RN, Griffiths A. Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of tumour necrosis factor-alpha antagonist therapy in Crohn's disease. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2009; 23:185-202. [PMID: 19319383 PMCID: PMC2694654 DOI: 10.1155/2009/201430] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Accepted: 01/08/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND Guidelines regarding the use of infliximab in Crohn's disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn's disease. METHODS A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn's disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn's disease is substantial and strengthened by results from longterm clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.
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Abstract
Tumor necrosis factor-alpha (TNFalpha) is a key proinflammatory cytokine involved in chronic inflammatory diseases. Infliximab, a chimeric (human-murine) monoclonal IgG1 anti-TNFalpha antibody, is used in the treatment of Crohn's disease (including fistulising disease) and rheumatoid arthritis (in combination with methotrexate) if standard treatments have failed. The indications for infliximab have recently been expanded to include ankylosing spondylitis, psoriatic arthritis, psoriasis and ulcerative colitis. The biological agent infliximab is given by multiple intravenous infusions in a dosage of 3-5 mg/kg (initially at weeks 0, 2 and 6; subsequently in intervals of 4-8 weeks). In controlled trials, clinical response rates of 20-40% have been achieved with such regimens in Crohn's disease and rheumatoid arthritis. However, the therapeutic benefits must be balanced against the risks of a variety of severe adverse events (e.g. severe infections including tuberculosis, hepatotoxicity, infusion reactions, serum sickness-like disease and lymphoma). Following single and multiple infusions of infliximab, no relevant differences in median concentration-time profiles have been observed between patients with Crohn's disease, patients with rheumatoid arthritis and patients with psoriasis. The apparent volume of distribution of the high-molecular-weight infliximab (149.1 kDa) is low (3-6L) and represents the intravascular space. The long persistence in this compartment (elimination half-life 7-12 days, mean residence time 12-17 days) is due to the very low systemic clearance of about 11-15 mL/hour (0.18-0.25 mL/minute). Elimination of infliximab is most probably accomplished through degradation by unspecific proteases. During multiple infusions (every 4-8 weeks), no accumulation was observed, and serum concentrations and the area under the plasma concentration-time curve of infliximab increased in proportion to the infused dose, indicating linear pharmacokinetics. Co-medication with methotrexate delayed the decline in the serum concentrations of infliximab. When relating serum concentrations to the clinical response in patients with rheumatoid arthritis and patients with Crohn's disease, it can be assumed that trough concentrations above 1 microg/mL could be used as a kind of therapeutic target. In the future, identification of biomarkers for (non-)response and risk factors for adverse drug reactions would be very helpful. Furthermore, combined biological, pharmacokinetic, pharmacogenomic and clinical studies have not yet been performed and are needed to optimise the therapeutic potential of infliximab, which is currently established as a rescue treatment in refractory patients.
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Affiliation(s)
- Ulrich Klotz
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
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