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Lewis TC, Hotchkis P, Wong A, Lamaina V, Fitzpatrick E, Stiefel A, Ohanian J, Schnier JR, Lesko M, Rudym D, Natalini JG, Angel LF. Comparison of Early Conversion to LCP-Tacrolimus (ENVARSUS XR) to Immediate-Release Tacrolimus in Lung Transplant Recipients. Clin Transplant 2025; 39:e70159. [PMID: 40294109 DOI: 10.1111/ctr.70159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/30/2025]
Abstract
Tacrolimus is highly effective at preventing allograft rejection and prolonging survival after lung transplantation. However, erratic pharmacokinetics may limit efficacy and predispose to greater adverse effects. We conducted a prospective, open-label trial of lung transplant recipients who underwent early conversion (within 30 days) to LCP tacrolimus (LCPT, n = 40) and compared first-year outcomes to an historical control of patients who remained on immediate-release tacrolimus (IRT, n = 24). Subjects were converted 1:1 from IRT to LCPT. The first dose of LCPT overlapped with the last morning dose of IRT. Conversion to LCPT occurred at a median of 17.5 [IQR 12-25] days. The conversion dose ratio was 1.0 mg:mg [IQR 0.75-1.50] at 14 days. At 1 year, there were no differences between LCPT and IRT in the incidence of biopsy-proven (12.5% vs. 25.0%, p = 0.30) or clinically treated (20.0% vs. 25.0%, p = 0.64) acute cellular rejection. However, the severity of any biopsy-proven rejection was significantly higher in the IRT cohort (27.5% vs. 54.2%, p = 0.03). Although not achieving statistical significance, de novo donor-specific antibodies were more commonly observed in the LCPT group (20.0% vs. 4.2%, p = 0.14). Despite this, the incidence of antibody-mediated rejection (7.5% vs. 0.0%, p = 0.29) and early-onset chronic lung allograft dysfunction (7.5% vs. 9.1%, p = 1.00) were similar. The incidence of chronic kidney disease stage 4 or greater at 1-year was similar (7.5% vs. 12.5%, p = 0.66). In conclusion, early conversion to LCPT was feasible and similarly efficacious to IRT in a cohort of lung transplant recipients. Trial Registration: ClinicalTrials.gov identifier: NCT04420195.
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Affiliation(s)
- Tyler C Lewis
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Perry Hotchkis
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Adrian Wong
- Department of Pharmacy, NYU Langone Health, New York, New York, USA
| | - Victoria Lamaina
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | | | - Avital Stiefel
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Juliana Ohanian
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Joseph R Schnier
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, NYU Langone Health, New York, New York, USA
| | - Melissa Lesko
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Darya Rudym
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Jake G Natalini
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Luis F Angel
- Transplant Institute, NYU Langone Health, New York, New York, USA
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Mora VM, Rodrigo E, Iturbe-Fernández D, Izquierdo S, Tello S, Benito-Hernández A, García-Saiz MM, San Segundo D, Francia MV, Cifrián JM. Exploring the Association Between Torquetenovirus Viral Load and Immunosuppressive Drug Exposure in Lung Transplantation. Biomolecules 2025; 15:494. [PMID: 40305234 PMCID: PMC12024801 DOI: 10.3390/biom15040494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/12/2025] [Accepted: 03/24/2025] [Indexed: 05/02/2025] Open
Abstract
To improve lung transplant recipient (LungTx) outcome, it would be of great interest to measure the net state of immunosuppression to avoid both infection and rejection. Measurement of Torquetenovirus load (TTV load) has been proposed as a biomarker to monitor solid organ transplantation, but its relationship with immunosuppressive drugs, particularly mycophenolic acid (MPA), is not well understood. We performed a prospective study of 53 LungTx, measuring TTV load before transplantation, at week 3, and at month 3. Tacrolimus and MPA doses and levels were recorded, and an area under the MPA curve (AUC-MPA) was calculated at the third month. LungTx in the fourth quartile of TTV load at the third week and the third month exhibited a low risk of acute rejection (OR 0.113, 95% CI 0.013-0.953, p = 0.045) and a high risk of opportunistic infection from month 3 to 6 (OR 15.200, 95% CI 1.525-151.511, p = 0.020), respectively. TTV load was weakly related to tacrolimus trough level at month 3 (rho = 0.283, p = 0.040). Neither MPA blood levels nor AUC-MPA were related to TTV load, although only patients with a reduction in MPA dose from month 1 to 3 showed a smaller increase in TTV load (0.86, IQR 2.58 log10 copies/mL vs. 2.26, IQR 3.02 log10 copies/mL, p = 0.026). In conclusion, TTV load in LungTx is only partially related to exposure to immunosuppressive drugs. Other variables, such as inflammation, immunosenescence, and frailty, may influence the overall level of immunosuppression and TTV load.
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Affiliation(s)
- Victor M. Mora
- Immunopathology Group, Respiratory Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain; (V.M.M.); (D.I.-F.); (S.I.); (S.T.); (J.M.C.)
| | - Emilio Rodrigo
- Immunopathology Group, Nephrology Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain;
| | - David Iturbe-Fernández
- Immunopathology Group, Respiratory Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain; (V.M.M.); (D.I.-F.); (S.I.); (S.T.); (J.M.C.)
| | - Sheila Izquierdo
- Immunopathology Group, Respiratory Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain; (V.M.M.); (D.I.-F.); (S.I.); (S.T.); (J.M.C.)
| | - Sandra Tello
- Immunopathology Group, Respiratory Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain; (V.M.M.); (D.I.-F.); (S.I.); (S.T.); (J.M.C.)
| | - Adalberto Benito-Hernández
- Immunopathology Group, Nephrology Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain;
| | - Maria Mar García-Saiz
- Clinical Pharmacology Department, Marqués de Valdecilla University Hospital-IDIVAL, 39005 Santander, Spain;
| | - David San Segundo
- Immunopathology Group, Immunology Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain;
| | - María Victoria Francia
- Infectious Diseases and Clinical Microbiology Group, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain;
| | - Jose M. Cifrián
- Immunopathology Group, Respiratory Department, Marqués de Valdecilla University Hospital-IDIVAL, University of Cantabria, 39005 Santander, Spain; (V.M.M.); (D.I.-F.); (S.I.); (S.T.); (J.M.C.)
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Jeong JC, Gelman AE, Chong AS. Update on the immunological mechanisms of primary graft dysfunction and chronic lung allograft dysfunction. Curr Opin Organ Transplant 2024; 29:412-419. [PMID: 39422603 PMCID: PMC11537820 DOI: 10.1097/mot.0000000000001175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
PURPOSE OF REVIEW Primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) are the leading causes of graft loss in lung transplant recipients. The development of mouse lung transplant models has allowed for the genetic dissection of cellular and molecular pathways that prevent graft survival. This review provides an overview into recent mechanistic insights into PGD and CLAD. RECENT FINDINGS Mouse orthotopic lung transplant models and investigations of human lung transplant recipeints have revealed new molecular and cellular targets that promote PGD and CLAD. Donor and recipient-derived innate immune cells promote PGD and CLAD. PGD is driven by communication between classical monocytes and tissue-resident nonclassical monocytes activating alveolar macrophages to release chemokines that recruit neutrophils. Products of cell damage trigger neutrophil NET release, which together with NK cells, antibodies and complement, that further promote PGD. The development of CLAD involves circuits that activate B cells, CD8 + T cells, classical monocytes, and eosinophils. SUMMARY Effective targeted management of PGD and CLAD in lung transplant recipient to improve their long-term outcome remains a critical unmet need. Current mechanistic studies and therapeutic studies in mouse models and humans identify new possibilities for prevention and treatment.
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Affiliation(s)
- Jong Cheol Jeong
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Surgery, Section of Transplantation, University of Chicago, Chicago, Illinois, USA
| | - Andrew E. Gelman
- Department of Surgery, Division of Cardiothoracic Surgery, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Anita S Chong
- Department of Surgery, Section of Transplantation, University of Chicago, Chicago, Illinois, USA
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Mineura K, Tanaka S, Goda Y, Terada Y, Yoshizawa A, Umemura K, Sato A, Yamada Y, Yutaka Y, Ohsumi A, Nakajima D, Hamaji M, Mennju T, Kreisel D, Date H. Fibrotic progression from acute cellular rejection is dependent on secondary lymphoid organs in a mouse model of chronic lung allograft dysfunction. Am J Transplant 2024; 24:944-953. [PMID: 38403187 PMCID: PMC11144565 DOI: 10.1016/j.ajt.2024.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 02/16/2024] [Accepted: 02/16/2024] [Indexed: 02/27/2024]
Abstract
Chronic lung allograft dysfunction (CLAD) remains one of the major limitations to long-term survival after lung transplantation. We modified a murine model of CLAD and transplanted left lungs from BALB/c donors into B6 recipients that were treated with intermittent cyclosporine and methylprednisolone postoperatively. In this model, the lung allograft developed acute cellular rejection on day 15 which, by day 30 after transplantation, progressed to severe pleural and peribronchovascular fibrosis, reminiscent of changes observed in restrictive allograft syndrome. Lung transplantation into splenectomized B6 alymphoplastic (aly/aly) or splenectomized B6 lymphotoxin-β receptor-deficient mice demonstrated that recipient secondary lymphoid organs, such as spleen and lymph nodes, are necessary for progression from acute cellular rejection to allograft fibrosis in this model. Our work uncovered a critical role for recipient secondary lymphoid organs in the development of CLAD after pulmonary transplantation and may provide mechanistic insights into the pathogenesis of this complication.
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Affiliation(s)
- Katsutaka Mineura
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Satona Tanaka
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Yasufumi Goda
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuriko Terada
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Akihiko Yoshizawa
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Keisuke Umemura
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Atsuyasu Sato
- Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshito Yamada
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yojiro Yutaka
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akihiro Ohsumi
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Daisuke Nakajima
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masatsugu Hamaji
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshi Mennju
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Daniel Kreisel
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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van Dommelen JEM, Grootjans H, Uijtendaal EV, Ruigrok D, Luijk B, van Luin M, Bult W, de Lange DW, Kusadasi N, Droogh JM, Egberts TCG, Verschuuren EAM, Sikma MA. Tacrolimus Variability and Clinical Outcomes in the Early Post-lung Transplantation Period: Oral Versus Continuous Intravenous Administration. Clin Pharmacokinet 2024; 63:683-693. [PMID: 38581638 PMCID: PMC11106167 DOI: 10.1007/s40262-024-01368-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND AND OBJECTIVE High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx. METHODS Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission. RESULTS We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9-14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI - 11.3 to - 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8-1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0-2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar. CONCLUSIONS Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection.
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Affiliation(s)
- Julia E M van Dommelen
- Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Heleen Grootjans
- Department of Internal Medicine, Section Nephrology, University Medical Center Groningen, Groningen, The Netherlands
- Department of Pulmonology, Tuberculosis and Lung Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Esther V Uijtendaal
- Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Dieuwertje Ruigrok
- Department of Pulmonary Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Bart Luijk
- Department of Pulmonary Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Matthijs van Luin
- Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Wouter Bult
- Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Dylan W de Lange
- Department of Intensive Care and Dutch Poisons Information Center, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Nuray Kusadasi
- Department of Intensive Care, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Joep M Droogh
- Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Toine C G Egberts
- Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Erik A M Verschuuren
- Department of Pulmonology, Tuberculosis and Lung Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Maaike A Sikma
- Department of Intensive Care and Dutch Poisons Information Center, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
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Du W, Wang X, Zhang D, Zuo X. Exploratory associations of tacrolimus exposure and clinical outcomes after lung transplantation: A retrospective, single center experience. Eur J Clin Pharmacol 2024; 80:747-757. [PMID: 38363388 DOI: 10.1007/s00228-024-03640-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/25/2024] [Indexed: 02/17/2024]
Abstract
PURPOSE This study aimed to investigate the potential impact of tacrolimus (TAC) exposure on clinical outcomes after lung transplantation. METHODS This retrospective observational study enrolled a total of 228 lung transplant recipients. TAC trough levels (C0) were collected for 3 intervals: 0-3 months, 3-12 months, and 12-24 months. The intra-patient variability (IPV) was calculated using coefficient of variation. Genotyping of CYP3A5*3 (rs776746) was performed. Patients were further divided into groups based on the C0 cut-off value of 8 ng/mL and IPV cut-off value of 30%. Cox proportional hazards regression models were used to explore the potential impact of C0 and IPV on outcomes of interests, including de-novo donor-specific antibodies (dnDSA), chronic lung allograft dysfunction (CLAD) and mortality. RESULTS The influence of CYP3A5*3 polymorphism was only significant for C0 and IPV during the first 3 months. Low C0 (< 8 ng/mL) at 3-12 months increased the risk of dnDSA (hazard ratio [HR] 2.696, 95% confidence interval [CI] 1.046-6.953) and mortality (HR 2.531, 95% CI 1.368-4.685), while High IPV (≥ 30%) during this period was associated with an increased risk of mortality (HR 2.543, 95% CI 1.336-4.839). Patients with Low C0/High IPV combination had significantly higher risks for dnDSA (HR 4.381, 95% CI 1.279-15.008) and survival (HR 6.179, 95% CI 2.598-14.698), surpassing the predictive power provided by C0 or IPV alone. CONCLUSION A combination of Low C0/High IPV might be considered in categorizing patients towards risk of adverse clinical outcomes following lung transplantation.
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Affiliation(s)
- Wenwen Du
- Department of Pharmacy, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Xiaoxing Wang
- Department of Pharmacy, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Dan Zhang
- Department of Pharmacy, China-Japan Friendship Hospital, Chaoyang District, Beijing, China
| | - Xianbo Zuo
- Department of Pharmacy, China-Japan Friendship Hospital, Chaoyang District, Beijing, China.
- Department of Dermatology, China-Japan Friendship Hospital, Chaoyang District, Beijing, China.
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Rodríguez-Espinosa D, Broseta JJ, Montagud-Marrahí E, Arana C, Ferrer J, Cuatrecasas M, Garcia-Criado Á, Amor AJ, Diekmann F, Ventura-Aguiar P. Tacrolimus's Time Below Therapeutic Range Is Associated With Acute Pancreatic Graft Rejection and the Development of De Novo Donor-specific Antibodies. Transpl Int 2024; 37:12591. [PMID: 38694489 PMCID: PMC11062183 DOI: 10.3389/ti.2024.12591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 03/11/2024] [Indexed: 05/04/2024]
Abstract
Tacrolimus is pivotal in pancreas transplants but poses challenges in maintaining optimal levels due to recipient differences. This study aimed to explore the utility of time spent below the therapeutic range and intrapatient variability in predicting rejection and de novo donor-specific antibody (dnDSA) development in pancreas graft recipients. This retrospective unicentric study included adult pancreas transplant recipients between January 2006 and July 2020. Recorded variables included demographics, immunosuppression details, HLA matching, biopsy results, dnDSA development, and clinical parameters. Statistical analysis included ROC curves, sensitivity, specificity, and predictive values. A total of 131 patients were included. Those with biopsy-proven acute rejection (BPAR, 12.2%) had more time (39.9% ± 24% vs. 25.72% ± 21.57%, p = 0.016) and tests (41.95% ± 13.57% vs. 29.96% ± 17.33%, p = 0.009) below therapeutic range. Specific cutoffs of 31.5% for time and 34% for tests below the therapeutic range showed a high negative predictive value for BPAR (93.98% and 93.1%, respectively). Similarly, patients with more than 34% of tests below the therapeutic range were associated with dnDSA appearance (38.9% vs. 9.4%, p = 0.012; OR 6.135, 1.346-27.78). In pancreas transplantation, maintaining optimal tacrolimus levels is crucial. Suboptimal test percentages below the therapeutic range prove valuable in identifying acute graft rejection risk.
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Affiliation(s)
- Diana Rodríguez-Espinosa
- Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - José Jesús Broseta
- Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Enrique Montagud-Marrahí
- Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Carolt Arana
- Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Joana Ferrer
- Department of Hepatobiliopancreatic Surgery and Liver Transplant, Hospital Clínic, Barcelona, Spain
| | | | | | - Antonio J. Amor
- Diabetes Unit, Department of Endocrinology and Nutrition, Hospital Clínic Barcelona, Barcelona, Spain
| | - Fritz Diekmann
- Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Pedro Ventura-Aguiar
- Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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8
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Walters S, Yerkovich S, Hopkins PM, Leisfield T, Winks L, Chambers DC, Divithotawela C. Erratic tacrolimus levels at 6 to 12 months post-lung transplant predicts poor outcomes. JHLT OPEN 2024; 3:100043. [PMID: 40145121 PMCID: PMC11935420 DOI: 10.1016/j.jhlto.2023.100043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Background It has previously been described that erratic tacrolimus blood levels are associated with graft failure in kidney and liver transplantation. Using a small cohort, we previously described that a higher tacrolimus standard deviation (SD) 6 to 12 months after lung transplantation increased the risk of chronic lung allograft dysfunction (CLAD) and death. We aimed to assess this in a larger cohort using the coefficient of variation (CoV) and identify potential risk factors for higher CoV. Methods We retrospectively reviewed 351 lung transplant recipients who received tacrolimus-based immunosuppression therapy. Cox proportional hazard modeling was used to investigate the effects of mean tacrolimus and CoV levels on survival and CLAD. Results Tacrolimus CoV from 6 to 12 months was independently associated with both CLAD (hazard ratio [HR], 19.99; 95% CI, 7.55-52.91; p < 0.001) and death (HR, 14.57; 95% (confidence interval) CI, 6.08-34.90; p < 0.001). Conversely, the mean trough tacrolimus blood concentration between 6 to 12 months was not associated with an increased risk of CLAD (HR, 0.94; 95% CI, 0.84-1.06; p = 0.34) or death (HR, 0.91; 95% CI, 0.82-1.01; p = 0.07). In a multivariable model, erratic tacrolimus levels were associated with antifungal use (β 0.10 95% CI 0.54-1.51, p < 0.001) and younger age (Î2 -0.0015, 95% CI -0.17 to -0.03, p = 0.005 per 5 years). Conclusions Erratic tacrolimus levels at 6 to 12 months post-lung transplant were associated with poor lung transplant outcomes. Future studies are required to determine whether interventions designed to optimize tacrolimus CoV could improve lung transplant outcomes.
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Affiliation(s)
| | - Stephanie Yerkovich
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Peter M Hopkins
- University of Queensland, Brisbane, Australia
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Trish Leisfield
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Lesleigh Winks
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Daniel C Chambers
- University of Queensland, Brisbane, Australia
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
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Morais MC, Soares ME, Costa G, Guerra L, Vaz N, Codes L, Bittencourt PL. Impact of tacrolimus intra-patient variability in adverse outcomes after organ transplantation. World J Transplant 2023; 13:254-263. [PMID: 37746041 PMCID: PMC10514747 DOI: 10.5500/wjt.v13.i5.254] [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] [Received: 06/28/2023] [Revised: 07/31/2023] [Accepted: 08/11/2023] [Indexed: 09/15/2023] Open
Abstract
Tacrolimus (Tac) is currently the most common calcineurin-inhibitor employed in solid organ transplantation. High intra-patient variability (IPV) of Tac (Tac IPV) has been associated with an increased risk of immune-mediated rejection and poor outcomes after kidney transplantation. Few data are available concerning the impact of high Tac IPV in non-kidney transplants. However, even in kidney transplantation, there is still a controversy whether high Tac IPV is indeed detrimental in respect to graft and/or patient survival. This may be due to different methods employed to evaluate IPV and distinct time frames adopted to assess graft and patient survival in those reports published up to now in the literature. Little is also known about the influence of high Tac IPV in the development of other untoward adverse events, update of the current knowledge regarding the impact of Tac IPV in different outcomes following kidney, liver, heart, lung, and pancreas tran splantation to better evaluate its use in clinical practice.
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Affiliation(s)
- Maria Clara Morais
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
| | - Maria Eduarda Soares
- School of Medicine, Federal University of Bahia, Salvador 40110-100, Bahia, Brazil
| | - Gabriela Costa
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
| | - Laura Guerra
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
| | - Nayana Vaz
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador 40130-030, Bahia, Brazil
| | - Liana Codes
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador 40130-030, Bahia, Brazil
| | - Paulo Lisboa Bittencourt
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador 40130-030, Bahia, Brazil
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10
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Evans KB, Beermann KJ, Lee HJ, Harris M, Frankel CW, Berry H, Ali HA. Impact of Tacrolimus Trough Variability on Acute Rejection Following Lung Transplantation. Transplant Proc 2022; 54:2270-2276. [PMID: 36123193 DOI: 10.1016/j.transproceed.2022.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Acute rejection is a risk factor for the development of chronic lung allograft dysfunction, the leading cause of morbidity and mortality in lung transplant recipients. Calcineurin inhibitors are the cornerstone of immunosuppression regimens after lung transplantation. METHODS We retrospectively evaluated the association of tacrolimus level variability with total acute rejection score at 12 months post-transplant. Secondary outcomes included the development of chronic lung allograft dysfunction and antibody-mediated rejection at 24months post-transplant. There were 229 lung transplant recipients included. RESULTS The mean (standard deviation) total rejection score of the cohort was 1.6 (1.7). Patients with high tacrolimus variability at 0 to 3, 3 to 6, and 6 to 12 months on average scored 0.18 (mean 1.6 vs 1.5; 95% CI): -0.3 to 0.66, P =.46), 0.14 (mean 1.7 vs 1.5; 95% CI: -0.32 to 0.6, P = .55), and 0.12 (mean 1.6 vs 1.5; 95% CI: -0.34 to 0.58, P = .62) point higher in 12-month total acute rejection scores, respectively; however, these differences were not statistically significant. The incidences of chronic lung allograft dysfunction and antibody-mediated rejection were numerically greater in the high variability group throughout certain periods; however, this was not consistent throughout all study timeframes and statistical significance was not evaluated. CONCLUSIONS High tacrolimus variability was not associated with increased 12-month total acute rejection score. Further studies are needed to assess long-term outcomes with tacrolimus level variability.
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Affiliation(s)
- Kayla B Evans
- Department of Pharmacy, Duke Health, Durham, North Carolina, United States
| | - Kristi J Beermann
- Department of Pharmacy, Duke Health, Durham, North Carolina, United States.
| | - Hui-Jie Lee
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States
| | - Matt Harris
- Department of Pharmacy, Duke Health, Durham, North Carolina, United States
| | - Courtney W Frankel
- Division of Pulmonary, Allergy and Critical Care, Duke Health, Durham, North Carolina, United States
| | - Holly Berry
- Department of Pharmacy, Duke Health, Durham, North Carolina, United States
| | - Hakim Azfar Ali
- Division of Pulmonary, Allergy and Critical Care, Duke Health, Durham, North Carolina, United States
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11
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Liu M, Shaver CM, Birdwell KA, Heeney SA, Shaffer CM, Van Driest SL. Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients. Pharmacogenet Genomics 2022; 32:209-217. [PMID: 35389944 PMCID: PMC9177686 DOI: 10.1097/fpc.0000000000000472] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D). METHODS We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed. RESULTS Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (P = 0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 (interquartile range: 147.6-267.5) (ng/ml)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), P = 0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes. CONCLUSION These data indicate that a composite CYP3A phenotype incorporating both increase and decrease variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.
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Affiliation(s)
- Michelle Liu
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ciara M. Shaver
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kelly A. Birdwell
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Stephanie A. Heeney
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Christian M. Shaffer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sara L. Van Driest
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Division of General Pediatrics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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12
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Duncan-Park S, Danziger-Isakov L, Armstrong B, Williams N, Odim J, Shemesh E, Sweet S, Annunziato R. Posttraumatic stress and medication adherence in pediatric transplant recipients. Am J Transplant 2022; 22:937-946. [PMID: 34837457 PMCID: PMC8897237 DOI: 10.1111/ajt.16896] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 01/25/2023]
Abstract
Adolescent transplant recipients may encounter a range of potentially traumatic events (PTEs) pre- and posttransplant, yet little is known about the relationship between posttraumatic stress symptoms (PTSS) and medication adherence in this population. In the present study, adolescent recipients and caregivers completed psychosocial questionnaires at enrollment. Outpatient tacrolimus trough level data were collected over 1 year to calculate the Medication Level Variability Index (MLVI), a measure of medication adherence. Nonadherence (MLVI ≥2) was identified in 34.8% of patients, and most (80.7%) reported ≥1 PTE exposure. Levels of PTSS indicating likely posttraumatic stress disorder (PTSD) were endorsed by 9.2% of patients and 43.7% of caregivers. PTSS and MLVI were significantly correlated in the liver subgroup (r = .30, p = .04). Hierarchical multivariable linear regression analyses revealed overall patient PTSS were significantly associated with QoL (p < .001). PTEs are common in adolescent recipients; a minority may meet criteria for PTSD. PTSS screening to identify nonadherence risk requires further investigation and addressing PTSS may improve QoL. Caregivers appear at greater risk for PTSD and may require their own supports. The study was approved by each participating center's Institutional Review Board.
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Affiliation(s)
- Sarah Duncan-Park
- Icahn School of Medicine at Mount Sinai, NY, NY
- Fordham University, Bronx, NY
| | | | | | | | | | | | | | - Rachel Annunziato
- Icahn School of Medicine at Mount Sinai, NY, NY
- Fordham University, Bronx, NY
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13
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The Role of Intra-Patient Variability of Tacrolimus Drug Concentrations in Solid Organ Transplantation: A Focus on Liver, Heart, Lung and Pancreas. Pharmaceutics 2022; 14:pharmaceutics14020379. [PMID: 35214111 PMCID: PMC8878862 DOI: 10.3390/pharmaceutics14020379] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 11/17/2022] Open
Abstract
Tacrolimus, the keystone immunosuppressive drug administered after solid organ transplantation, presents a narrow therapeutic index and wide inter- and intra-patient pharmacokinetic variability (IPV). The latter has been fairly studied in kidney transplantation, where it could impact outcomes. However, literature about other transplanted organ recipients remains inconclusive. This review aimed at summarizing the evidence about the IPV of tacrolimus concentrations outside of the scope of kidney transplantation. First, factors influencing IPV will be presented. Then, the potential of IPV as a biomarker predictive of graft outcomes will be discussed in liver, heart, lung and pancreas transplantation. Lastly, strategies to reduce IPV will be reviewed, with the ultimate objective being ready-to-implement solutions in clinical practice by transplantation professionals.
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14
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González-Vílchez F, Crespo-Leiro MG, Delgado-Jiménez J, Pérez-Villa F, Segovia-Cubero J, Díaz-Molina B, Mirabet-Pérez S, Arizón del Prado JM, Blasco-Peiró T, Martínez-Sellés M, Almenar-Bonet L, Garrido-Bravo I, Rábago G, Vázquez de Prada JA. Impacto de la variabilidad intrapaciente en la concentración sanguínea de anticalcineurínicos en los resultados del trasplante cardiaco. Rev Esp Cardiol 2022. [DOI: 10.1016/j.recesp.2021.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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15
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González-Vílchez F, Crespo-Leiro MG, Delgado-Jiménez J, Pérez-Villa F, Segovia-Cubero J, Díaz-Molina B, Mirabet-Pérez S, Arizón Del Prado JM, Blasco-Peiró T, Martínez-Sellés M, Almenar-Bonet L, Garrido-Bravo I, Rábago G, Vázquez de Prada JA. Impact of intrapatient blood level variability of calcineurin inhibitors on heart transplant outcomes. REVISTA ESPANOLA DE CARDIOLOGIA (ENGLISH ED.) 2022; 75:129-140. [PMID: 33744197 DOI: 10.1016/j.rec.2021.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/08/2021] [Indexed: 06/12/2023]
Abstract
INTRODUCTION AND OBJECTIVES Intrapatient blood level variability (IPV) of calcineurin inhibitors has been associated with poor outcomes in solid-organ transplant, but data for heart transplant are scarce. Our purpose was to ascertain the clinical impact of IPV in a multi-institutional cohort of heart transplant recipients. METHODS We retrospectively studied patients aged ≥18 years, with a first heart transplant performed between 2000 and 2014 and surviving≥ 1 year. IPV was assessed by the coefficient of variation of trough levels from posttransplant months 4 to 12. A composite of rejection or mortality/graft loss or rejection and all-cause mortality/graft loss between years 1 to 5 posttransplant were analyzed by Cox regression analysis. RESULTS The study group consisted of 1581 recipients (median age, 56 years; women, 21%). Cyclosporine immediate-release tacrolimus and prolonged-release tacrolimus were used in 790, 527 and 264 patients, respectively. On multivariable analysis, coefficient of variation> 27.8% showed a nonsignificant trend to association with 5-year rejection-free survival (HR, 1.298; 95%CI, 0.993-1.695; P=.056) and with 5-year mortality (HR, 1.387; 95%CI, 0.979-1.963; P=.065). Association with rejection became significant on analysis of only those patients without rejection episodes during the first year posttransplant (HR, 1.609; 95%CI, 1.129-2.295; P=.011). The tacrolimus-based formulation had less IPV than cyclosporine and better results with less influence of IPV. CONCLUSIONS IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients.
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Affiliation(s)
| | - María G Crespo-Leiro
- Servicio de Cardiología, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
| | - Juan Delgado-Jiménez
- Servicio Cardiología y Fundación Investigación Hospital Universitario 12 de Octubre, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Félix Pérez-Villa
- Servicio de Cardiología, Hospital Clínic Universitari, Barcelona, Spain
| | - Javier Segovia-Cubero
- Servicio de Cardiología, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
| | - Beatriz Díaz-Molina
- Servicio de Cardiología, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
| | - Sonia Mirabet-Pérez
- Servei de Cardiologia, Hospital Universitari Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Teresa Blasco-Peiró
- Servicio de Cardiología, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Manuel Martínez-Sellés
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Servicio de Cardiología, Hospital Universitario Gregorio Marañón, Madrid, Spain; Facultad de Medicina, Universidad Europea, Madrid, Spain; Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Luis Almenar-Bonet
- Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Iris Garrido-Bravo
- Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
| | - Gregorio Rábago
- Servicio de Cirugía Cardiaca, Clínica Universitaria de Navarra, Pamplona, Spain
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16
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Del Bello A, Gaible C, Longlune N, Hebral AL, Esposito L, Gandia P, Kamar N. Tacrolimus Intrapatient Variability After Switching From Immediate or Prolonged-Release to Extended-Release Formulation, After an Organ Transplantation. Front Pharmacol 2021; 12:602764. [PMID: 34690747 PMCID: PMC8529208 DOI: 10.3389/fphar.2021.602764] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 07/26/2021] [Indexed: 01/06/2023] Open
Abstract
Background and Purpose: Several formulations of tacrolimus are available, but evidence of the benefit of changing to the most recent formulations is lacking. Tacrolimus intra-patient variability (tacrolimus IPV) is an emerging risk factor associated with poor graft outcomes after solid organ transplantations. Here, we examined the modifications of tacrolimus IPV after switching to a different formulation of tacrolimus. Experimental Approach: We identified 353 solid organ transplant recipients that were switched in our center from immediate-release (IR-tacrolimus) or prolonged-release tacrolimus (PR-tacrolimus) to extended-release, LCP-tacrolimus (LCP-tacrolimus). Among them, 54 patients underwent at least 3 available tacrolimus blood concentrations before and after the switch, allowing us to investigate tacrolimus IPV. Key Results: The switch was considered as a safe procedure since only four of the 353 patients presented a graft rejection after the switch, and no patient was hospitalized for tacrolimus overdose. The tacrolimus IPV estimated by the coefficient of variation (CV-IPV) was stable before and after the switch to LCP-tacrolimus (CV-IPV: 29.0% (IQR 25-75 (15.5; 38.5) before and 24.0% (15.8; 36.5) after the switch, p = 0.65). Conclusion and Implications: Switching from IR- or PR-tacrolimus to LCP-tacrolimus is a safe procedure. However, the CV-tacrolimus IPV was not impacted by the change of formulation.
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Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - Clotilde Gaible
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Nathalie Longlune
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Anne-Laure Hebral
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Laure Esposito
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Peggy Gandia
- Pharmacokinetics and Toxicology Laboratory, Toulouse University Hospital, Toulouse, France.,INTHERES, INRAE, ENVT, Université de Toulouse, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France
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17
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Duncan-Park S, Dunphy C, Becker J, D’Urso C, Annunziato R, Blatter J, Conrad C, Goldfarb SB, Hayes D, Melicoff E, Schecter M, Visner G, Armstrong B, Chin H, Kesler K, Williams NM, Odim JN, Sweet SC, Danziger-Isakov L, Shemesh E. Remote intervention engagement and outcomes in the Clinical Trials in Organ Transplantation in Children consortium multisite trial. Am J Transplant 2021; 21:3112-3122. [PMID: 33752251 PMCID: PMC8856090 DOI: 10.1111/ajt.16567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/03/2021] [Accepted: 02/23/2021] [Indexed: 01/25/2023]
Abstract
Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ≥2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow-up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended. Outcomes were defined before the intent-to-treat analysis. Feasibility was defined as ≥50% of participants completing the weekly calls. MLVI was compared pre- and 180 days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison. Seventy-five percent of participants completed ≥3 weekly calls; average time on protocol was 257.7 days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180 days postenrollment (2.9 ± 1.29) compared with pre-enrollment (4.6 ± 2.10), p = .02. At 180 days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group (p = .054). Participants successfully engaged in a long-term remote intervention, and their medication blood levels stabilized. NCT02266888.
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Affiliation(s)
- Sarah Duncan-Park
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
- Fordham University, Department of Psychology, Bronx, New York
| | - Claire Dunphy
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
- Fordham University, Department of Psychology, Bronx, New York
| | - Jacqueline Becker
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
| | - Christine D’Urso
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
| | - Rachel Annunziato
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
- Fordham University, Department of Psychology, Bronx, New York
| | | | - Carol Conrad
- Lucille Packard Children’s Hospital, Palo Alto, California
| | | | - Don Hayes
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | | | - Marc Schecter
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | - Gary Visner
- Boston Children’s Hospital, Boston, Massachusetts
| | | | | | | | | | - Jonah N Odim
- National Institutes of Health, NIAID, Bethesda, Maryland
| | | | | | - Eyal Shemesh
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
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18
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Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation. Clin Pharmacokinet 2021; 59:403-408. [PMID: 31820394 PMCID: PMC7109168 DOI: 10.1007/s40262-019-00846-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The calcineurin inhibitor tacrolimus is an effective immunosuppressant and is extensively used in solid organ transplantation. In the first week after heart and lung transplantation, tacrolimus dosing is difficult due to considerable physiological changes because of clinical instability, and toxicity often occurs, even when tacrolimus concentrations are within the therapeutic range. The physiological and pharmacokinetic changes are outlined. Excessive variability in bioavailability may lead to higher interoccasion (dose-to-dose) variability than interindividual variability of pharmacokinetic parameters. Intravenous tacrolimus dosing may circumvent this high variability in bioavailability. Moreover, the interpretation of whole-blood concentrations is discussed. The unbound concentration is related to hematocrit, and changes in hematocrit may increase toxicity, even within the therapeutic range of whole-blood concentrations. Therefore, in clinically unstable patients with varying hematocrit, aiming at the lower therapeutic level is recommended and tacrolimus personalized dosing based on hematocrit-corrected whole-blood concentrations may be used to control the unbound tacrolimus plasma concentrations and subsequently reduce toxicity.
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19
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Schumacher L, Leino AD, Park JM. Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective. Pharmacotherapy 2020; 41:103-118. [PMID: 33131078 DOI: 10.1002/phar.2480] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/21/2020] [Accepted: 09/26/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. METHODS A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. RESULTS Forty-four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV-directed interventions was limited to small preliminary studies. CONCLUSIONS High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV-directed interventions to improve transplant outcomes.
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Affiliation(s)
| | - Abbie D Leino
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Jeong M Park
- Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA.,Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
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20
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Sikma MA, Hunault CC, Van Maarseveen EM, Huitema ADR, Van de Graaf EA, Kirkels JH, Verhaar MC, Grutters JC, Kesecioglu J, De Lange DW. High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation. Eur J Drug Metab Pharmacokinet 2020; 45:123-134. [PMID: 31745812 PMCID: PMC6994432 DOI: 10.1007/s13318-019-00591-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background and Objective Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation. Methods We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC–MS/MS) and analysed via population pharmacokinetic modelling. Results The concentration–time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2–22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199–267) and 521 L (95% CI 441–634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5–64.4). Conclusions The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24. Electronic supplementary material The online version of this article (10.1007/s13318-019-00591-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Maaike A Sikma
- Department of Intensive Care and Dutch Poisons Information Center, University Medical Center Utrecht, Utrecht University, F06.149, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
| | - Claudine C Hunault
- Dutch Poisons Information Center, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Erik M Van Maarseveen
- Department of Clinical Pharmacy, Princess Máxima Center, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.,Department of Clinical Pharmacy, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Alwin D R Huitema
- Department of Clinical Pharmacy, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.,Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ed A Van de Graaf
- Department of Lung Transplantation, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Johannes H Kirkels
- Department of Cardiology, Heart Transplantation, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Jan C Grutters
- Department of Lung Transplantation, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.,Department of Pulmonology, St. Antonius Hospital, Nieuwegein, Utrecht, The Netherlands
| | - Jozef Kesecioglu
- Department of Intensive Care, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Dylan W De Lange
- Dutch Poisons Information Center and Department of Intensive Care, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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21
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Tacrolimus monitoring parameters are not associated with acute cellular rejection following lung transplantation. Eur J Clin Pharmacol 2020; 77:63-69. [PMID: 32803287 DOI: 10.1007/s00228-020-02976-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/01/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE The purpose of this study was to evaluate the impact of tacrolimus drug monitoring parameters on the incidence of acute cellular rejection (ACR) in lung transplant recipients (LTRs). METHODS This was a retrospective study of patients who underwent lung transplantation at a single center. LTRs who were given tacrolimus during the first 6 months after transplantation and who underwent at least one bronchoscopy with biopsy were included. Tacrolimus time in therapeutic range (TTR) was calculated using Rosendaal's method. Time to therapeutic level, coefficient of variance (CoV), and median trough concentrations were also determined. RESULTS The study included 157 LTRs. ACR ≥ A1 grade was present in 46.5% of patients, and ACR ≥ A2 grade was present in 17.2%. There was no difference between tacrolimus TTR in patients with ACR ≥ A1 compared with those without ACR (47.4 ± 16.1 versus 46.2 ± 18.9%, p = 0.67) or in patients with ACR ≥ A2 grade compared with those with A0 or A1 ACR (46.0 ± 16.3 versus 47.0 ± 17.9%, p = 0.81). When comparing patients with any ACR grade A1 or higher with those without ACR, there was no difference in tacrolimus CoV (42.7 ± 11.0 versus 44.6 ± 12.4, p = 0.30), median tacrolimus trough concentration (9.9 ± 1.3 versus 9.8 ± 1.4 ng/mL, p = 0.66), or days to therapeutic level (9 versus 12 days, p = 0.057). CONCLUSIONS The results suggest that tacrolimus TTR, time in therapeutic range, and variability are not related to the presence of ACR in LTRs.
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22
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Kolaitis NA, Calabrese DR, Ahearn P, Venado A, Florez R, Lei HL, Isaak K, Henricksen E, Martinez E, Chong T, Shah RJ, Leard LE, Kleinhenz ME, Golden J, De Marco T, Greenland JR, Kukreja J, Hays SR, Blanc PD, Singer JP. Tacrolimus trough monitoring guided by mass spectrometry without accounting for assay differences is associated with acute kidney injury in lung transplant recipients. Am J Health Syst Pharm 2020; 76:2019-2027. [PMID: 31696925 DOI: 10.1093/ajhp/zxz243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Tacrolimus is a nephrotoxic immunosuppressant historically monitored via enzyme-based immunoassay (IA). After 2011, the 2 largest laboratory companies in the United States implemented tacrolimus quantification by liquid chromatography-mass spectrometry (LC-MS); this method excludes metabolites, potentially resulting in lower quantified drug concentrations. We sought to determine if tacrolimus therapeutic drug monitoring via LC-MS, as performed using trough targets originally derived from IA values, influences clinical outcomes. METHODS In a single-center retrospective cohort study of lung transplant recipients, risks of acute kidney injury, acute renal failure, and new-onset diabetes after transplantation, as well as chronic lung allograft dysfunction-free survival, were compared in 82 subjects monitored by LC-MS and 102 subjects monitored by IA using Cox proportional hazard models adjusted for age, sex, baseline renal function, and race. RESULTS LC-MS-based monitoring was associated with a greater risk of acute kidney injury (adjusted hazard ratio, 1.65; 95% confidence interval, 1.02-2.67). No statistically significant differences in risks of acute renal failure and new-onset diabetes after transplantation were observed. CONCLUSION Although LC-MS provides a more accurate representation of the blood concentration of the parent compound tacrolimus exclusive of metabolite, established cut points for tacrolimus dosing may need to be adjusted to account for the increased risk of renal injury.
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Affiliation(s)
- Nicholas A Kolaitis
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Daniel R Calabrese
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Patrick Ahearn
- Division of Nephrology, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Aida Venado
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Rebecca Florez
- School of Pharmacy and School of Medicine, University of California, San Francisco, San Francisco, CA
| | - Huey-Ling Lei
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Karolina Isaak
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Erik Henricksen
- School of Pharmacy and School of Medicine, University of California, San Francisco, CA
| | - Emily Martinez
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Tiffany Chong
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Rupal J Shah
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Lorriana E Leard
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Mary Ellen Kleinhenz
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Jeffrey Golden
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Teresa De Marco
- Division of Cardiology, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - John R Greenland
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA, and Division of Pulmonary and Critical Care Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA
| | - Jasleen Kukreja
- Division of Thoracic Surgery, Department of Surgery, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Steven R Hays
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Paul D Blanc
- Division of Pulmonary and Critical Care and Division of Occupational and Environmental Medicine, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
| | - Jonathan P Singer
- Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA
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23
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Miano TA, Flesch JD, Feng R, Forker CM, Brown M, Oyster M, Kalman L, Rushefski M, Cantu E, Porteus M, Yang W, Localio AR, Diamond JM, Christie JD, Shashaty MGS. Early Tacrolimus Concentrations After Lung Transplant Are Predicted by Combined Clinical and Genetic Factors and Associated With Acute Kidney Injury. Clin Pharmacol Ther 2020; 107:462-470. [PMID: 31513279 PMCID: PMC6980920 DOI: 10.1002/cpt.1629] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 08/25/2019] [Indexed: 12/13/2022]
Abstract
Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.
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Affiliation(s)
- Todd A. Miano
- Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania
| | - Judd D. Flesch
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Rui Feng
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania
| | - Caitlin M. Forker
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Melanie Brown
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Michelle Oyster
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Laurel Kalman
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Melanie Rushefski
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Edward Cantu
- Division of Cardiovascular Surgery, Perelman School of Medicine at the University of Pennsylvania
| | - Mary Porteus
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Wei Yang
- Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania
| | - A. Russel Localio
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania
| | - Joshua M. Diamond
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Jason D. Christie
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
| | - Michael G. S. Shashaty
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania
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24
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Bertram A, Fuge J, Suhling H, Tudorache I, Haverich A, Welte T, Gottlieb J. Adherence is associated with a favorable outcome after lung transplantation. PLoS One 2019; 14:e0226167. [PMID: 31846463 PMCID: PMC6917262 DOI: 10.1371/journal.pone.0226167] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023] Open
Abstract
Non-adherence to therapy is associated with impaired outcome in solid organ allograft recipients. Outcome data are limited after lung transplantation. In a single-center cohort study, adherence was assessed in 427 patients undergoing lung transplantation from 2010 to 2013. Objective criteria of adherence were judged by health care workers on every visit on a five item Likert scale including trough level monitoring, home spirometry and contact with an overall rating of adherence between 0 and 100%. Cut-off values for good vs. suboptimal adherence were defined retrospectively. Primary outcome was allograft survival, secondary outcomes were patient survival, prevalence of chronic lung allograft dysfunction, hospitalizations, renal function and quality of life. Follow-up ended on 31st December 2018. Median adherence was 86% on 6,623 visits, this cut-off was used as a discriminator between good and suboptimal adherers. Patients with good adherence within the first three years showed better 5-year allograft (74% vs. 60%, p = 0.003) and patient survival (79% vs. 64%, p<0.001) and lower prevalence of chronic allograft dysfunction (33% vs. 45%, p = 0.011) after 5 years compared to patients with suboptimal adherence. A multidimensional adherence score proved to be a simple tool to assess adherence in clinical practice. Suboptimal adherence was associated with impaired outcome in lung transplant patients.
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Affiliation(s)
- Anna Bertram
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
- * E-mail:
| | - Jan Fuge
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
| | - Hendrik Suhling
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
| | - Igor Tudorache
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Axel Haverich
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Tobias Welte
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
| | - Jens Gottlieb
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
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25
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A Novel, Dose-Adjusted Tacrolimus Trough-Concentration Model for Predicting and Estimating Variance After Kidney Transplantation. Drugs R D 2019; 19:201-212. [PMID: 31073875 PMCID: PMC6544741 DOI: 10.1007/s40268-019-0271-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background and Objective Given that a high intrapatient variability (IPV) of tacrolimus whole blood concentration increases the risk for a poor kidney transplant outcome, some experts advocate routine IPV monitoring for detection of high-risk patients. However, attempts to estimate the variance of tacrolimus trough concentrations (TTC) are limited by the need for patients to receive a fixed dose over time and/or the use of linear statistical models. A goal of this study is to overcome the current limitations through the novel application of statistical methodology generalizing the relationship between TTC and dose through the use of nonparametric functional regression modeling. Methods With TTC as a response and dose as a covariate, the model employs an unknown bivariate function, allowing for the potentially complex, nonlinear relationship between the two parameters. A dose-adjusted variance of TTC is then derived based on standard functional principal component analysis (FPCA). To assess the model, it was compared against an FPCA-based model and linear mixed-effects models using prediction error, bias, and coverage probabilities for simulated data as well as phase III data from the Astellas new drug application studies for extended-release tacrolimus. Results Our numerical investigation indicates that the new model better predicts dose-adjusted TTCs compared with the prediction of linear mixed effects models. Estimated coverage probabilities also indicate that the new model accurately accounts for the variance of TTC during the periods of large fluctuation in dose, whereas the linear mixed effects model consistently underestimates the coverage probabilities because of the inaccurate characterization of TTC fluctuation. Conclusion This is the first known application of a functional regression model to assess complex relationships between TTC and dose in a real clinical setting. This new method has applicability in future clinical trials including real-world data sets due to flexibility of the nonparametric modeling approach. Electronic supplementary material The online version of this article (10.1007/s40268-019-0271-2) contains supplementary material, which is available to authorized users.
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26
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Kwiatkowska E, Kwiatkowski S, Wahler F, Gryczman M, Domańki L, Marchelk-Myśliwiec M, Ciechanowski K, Drozd-Dabrowska M. C/D Ratio in Long-Term Renal Function. Transplant Proc 2019; 51:3265-3270. [PMID: 31732210 DOI: 10.1016/j.transproceed.2019.08.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 07/22/2019] [Accepted: 08/17/2019] [Indexed: 11/24/2022]
Abstract
BACKGROUND/AIMS Tacrolimus is an immunosuppressive drug. Its C0 concentration, commonly used for monitoring, does not always correspond to its pharmacologic effect. Thölking et al developed an indicator, the C/D ratio, that describes the drug's metabolism rate. Our purpose was to determine whether the points dividing the patients into fast, intermediate, and slow metabolizers that were assumed by those authors would be similar for long-term follow-up after renal transplantation (RTx). METHODS We examined the C/D ratio in 571 patients at their most recent appointments-1 year and more after renal transplantation. The mean time after RTx was 84 months. We studied kidney function both at the most recent appointment and early after RTx. RESULTS The median C/D ratio for our group was 1.68. Our observations revealed a negative correlation between the C/D ratio and creatinine concentration and a positive correlation between the C/D ratio and eGFR concentration long term after RTx. We formulated a C/D ratio cutoff point between an eGFR < and ≥ 60 mL/min/1.73 m2 and came up with the value of 1.53. It was found that between the < 1.53 and ≥ 1.53 groups, there were significant differences in creatinine and eGFR concentrations at the most recent appointment, as well as differences in how creatinine and eGFR levels varied over time between RTx and the most recent observation. CONCLUSIONS The C/D ratio is useful for assessing the effect of the tacrolimus metabolism rate on long-term renal function. We propose the C/D ratio value of 1.53 as the cutoff point below which the ratio provides a negative prognosis for long-term renal function.
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Affiliation(s)
- Ewa Kwiatkowska
- Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland.
| | - Sebastian Kwiatkowski
- Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland
| | - Fabienne Wahler
- Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Marta Gryczman
- Department of Nephrology, Independent Public State Integrated Hospital, Szczecin, Poland
| | - Leszek Domańki
- Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Małgorzata Marchelk-Myśliwiec
- Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Kazimierz Ciechanowski
- Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Marzena Drozd-Dabrowska
- Department of Epidemiology and Management, Faculty of Health Sciences, Pomeranian Medical Univeristy, Szczecin, Poland
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27
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Kuypers DRJ. Intrapatient Variability of Tacrolimus Exposure in Solid Organ Transplantation: A Novel Marker for Clinical Outcome. Clin Pharmacol Ther 2019; 107:347-358. [PMID: 31449663 DOI: 10.1002/cpt.1618] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/14/2019] [Indexed: 12/12/2022]
Abstract
The calcineurin-inhibitor tacrolimus (Tac) provides an acceptable balance between prevention of allograft rejection and drug-related adverse effects, making it the standard of care in all types of solid organ transplantation for the last 2 decades. Recent data have demonstrated that high intrapatient variability (IPV) in Tac predose trough concentrations has deleterious effects on allograft survival. The underlying mechanisms by which a high Tac IPV shortens allograft survival are acute and chronic rejection, donor-specific anti-HLA antibodies, and progressive fibrotic damage to the graft. Modifiable causes of high Tac IPV include medication nonadherence (MNA), drug interactions, nutritional interferences, and concurrent diseases. Recognizing high Tac IPV as an important prognostic risk factor after solid organ transplantation requires understanding of the definitions, the use of correct diagnostic metrics, and methodology. Therapeutic interventions aimed at reducing Tac IPV are targeted on improving MNA, avoiding or adjusting drug interactions, drug dosing assists, and educational support of recipients.
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Affiliation(s)
- Dirk R J Kuypers
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.,Department of Microbiology and Immunology, Catholic University of Leuven, Leuven, Belgium
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28
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Leino AD, King EC, Jiang W, Vinks AA, Klawitter J, Christians U, Woodle ES, Alloway RR, Rohan JM. Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values. Am J Transplant 2019; 19:1410-1420. [PMID: 30506623 DOI: 10.1111/ajt.15199] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/14/2018] [Accepted: 11/26/2018] [Indexed: 01/25/2023]
Abstract
The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.
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Affiliation(s)
- Abbie D Leino
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Eileen C King
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Biostatistics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Wenlei Jiang
- Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food & Drug Administration, Silver Spring, Maryland
| | - Alexander A Vinks
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jost Klawitter
- iC42 Clinical Research and Development, University of Colorado, Aurora, Colorado
| | - Uwe Christians
- iC42 Clinical Research and Development, University of Colorado, Aurora, Colorado
| | - E Steve Woodle
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Rita R Alloway
- Division of Nephrology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jennifer M Rohan
- Division of Hematology and Oncology, Children's Hospital of Richmond, Richmond, Virginia
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29
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Darley DR, Carlos L, Hennig S, Liu Z, Day R, Glanville AR. Tacrolimus exposure early after lung transplantation and exploratory associations with acute cellular rejection. Eur J Clin Pharmacol 2019; 75:879-888. [PMID: 30859243 DOI: 10.1007/s00228-019-02658-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 02/27/2019] [Indexed: 12/18/2022]
Abstract
AIMS To (i) describe tacrolimus (TAC) pre-dose concentrations (C0), (ii) calculate apparent oral TAC clearance (CL/FHCT) adjusted for measured haematocrit (HCTi) and standardised to a HCT of 45%, across three observation time points and (iii) explore if low TAC C0 or high mean CL/FHCT are associated with an increased risk of rejection episodes early after lung transplantation. METHODS TAC whole blood concentration-time profiles and transbronchial biopsies were performed prospectively at weeks 3, 6 and 12 after lung transplantation. The TAC pre-dose concentration (C0) was measured, and CL/FHCT was determined using non-compartmental analysis. The associations between TAC C0 and CL/FHCT and rejection status were explored using repeated measures logistic regression. RESULTS Eighteen patients provided 377 TAC whole blood concentrations. Considerable variability around the median (IQR) CL/FHCT 6.8 (4.2-15.9) L h-1, and the median C0 12.7 (9.9-16.6) μg L-1 was noted. Despite adjustment for haematocrit, a significant decrease was observed in CL/FHCT in all patients over time: CL/FHCT 14 (5.4-23) at week 3, CL/FHCT 7.7 (4.5-12) at week 6 and CL/FHCT 3.9 (2.4-11) L h-1 at week 12 (p < 0.01). Seven (38.9%) patients experienced a single grade 2 rejection, whilst 11 (61.1%) patients experienced no rejection. Higher TAC C0 were associated with a reduced risk of rejection OR 0.68 (95% CI 0.51-0.91, p = 0.02), and greater mean CL/FHCT was associated with an increased risk of rejection OR 1.34 (95% CI 1.01-1.81 p = 0.04). CONCLUSION Monitoring TAC C0, HCT and CL/FHCT in patients after lung transplantation may assist clinicians in detecting patients at risk of acute rejection and may guide future research into TAC and HCT monitoring after lung transplantation.
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Affiliation(s)
- David R Darley
- Lung Transplant Unit, St Vincent's Hospital Darlinghurst, Sydney, Australia. .,UNSW Medicine, St Vincent's Hospital Clinical School, Sydney, Australia.
| | - Lilibeth Carlos
- Department of Pharmacy, St Vincent's Hospital Darlinghurst, Sydney, Australia
| | - Stefanie Hennig
- School of Pharmacy, University of Queensland, Brisbane, Australia
| | - Zhixin Liu
- Department of Statistics, University of New South Wales, Kensington, Australia
| | - Richard Day
- UNSW Medicine, St Vincent's Hospital Clinical School, Sydney, Australia.,Department of Clinical Pharmacology, St Vincent's Hospital Darlinghurst, Sydney, Australia
| | - Allan R Glanville
- Lung Transplant Unit, St Vincent's Hospital Darlinghurst, Sydney, Australia
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Ryu JH, Choi S, Lee HJ, Kim YT, Kim YW, Yang J. Low early posttransplant serum tacrolimus levels are associated with poor patient survival in lung transplant patients. Ann Thorac Med 2019; 14:186-191. [PMID: 31333768 PMCID: PMC6611203 DOI: 10.4103/atm.atm_160_18] [Citation(s) in RCA: 6] [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] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND: Low-dose tacrolimus-based immunosuppression is a standard therapy in kidney and liver transplantation; however, the optimal therapeutic level of tacrolimus has not been established in lung transplantation. We aimed to identify the tacrolimus level associated with better outcomes in lung transplant patients. METHODS: This retrospective study included patients who underwent lung transplantation at Seoul National University Hospital between 2006 and 2016. Kaplan–Meier survival analysis and Cox regression were performed according to tacrolimus levels at several time-points within 1-year posttransplantation. RESULTS: A total of 43 patients received bilateral lung transplantation. The median age was 53 years and the median follow-up was 20.5 months. Overall and 1-year patient survival rates were 55.8% and 74.4%, respectively. Infection was the most common cause of death (78.9%). Chronic lung allograft dysfunction was observed in 16.3%. A tacrolimus level <9 ng/ml at 1 month was associated with lower rejection-free survival (P = 0.009). A time-averaged tacrolimus level <10 ng/ml within 1 month posttransplantation was an independent risk factor for poor patient survival (hazard ratio: 4.904; 95% confidence interval: 1.930–12.459; P= 0.001). Furthermore, higher tacrolimus levels did not increase infectious complications. CONCLUSIONS: These finding suggest that tacrolimus levels ≥10 ng/ml within 1 month after lung transplantation appear to be associated with better patient survival.
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Affiliation(s)
- Jung-Hwa Ryu
- Transplant Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sunmi Choi
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyun Joo Lee
- Department of Thoracic Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Young Tae Kim
- Department of Thoracic Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Young Whan Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jaeseok Yang
- Transplant Center, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
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Parker WF, Bag R. Chronic Lung Allograft Dysfunction. CURRENT PULMONOLOGY REPORTS 2018. [DOI: 10.1007/s13665-018-0208-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Calabrese DR, Florez R, Dewey K, Hui C, Torgerson D, Chong T, Faust H, Rajalingam R, Hays SR, Golden JA, Kukreja J, Singer JP, Greenland JR. Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients. Clin Transplant 2018; 32:e13332. [PMID: 29920787 DOI: 10.1111/ctr.13332] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2018] [Indexed: 12/18/2022]
Abstract
Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C0 /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C0 /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.
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Affiliation(s)
- Daniel R Calabrese
- Department of Medicine, University of California, San Francisco, California
| | - Rebecca Florez
- Department of Clinical Pharmacy, University of California, San Francisco, California
| | - Katherine Dewey
- Department of Clinical Pharmacy, University of California, San Francisco, California
| | - Christine Hui
- Department of Clinical Pharmacy, University of California, San Francisco, California
| | - Dara Torgerson
- Department of Medicine, University of California, San Francisco, California
| | - Tiffany Chong
- Department of Medicine, University of California, San Francisco, California
| | - Hilary Faust
- Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Raja Rajalingam
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, California
| | - Steven R Hays
- Department of Medicine, University of California, San Francisco, California
| | - Jeffrey A Golden
- Department of Medicine, University of California, San Francisco, California
| | - Jasleen Kukreja
- Department of Surgery, University of California, San Francisco, California
| | - Jonathan P Singer
- Department of Medicine, University of California, San Francisco, California
| | - John R Greenland
- Department of Medicine, University of California, San Francisco, California.,Medical Service, Veterans Affairs Health Care System, San Francisco, California
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Ensor CR, Iasella CJ, Harrigan KM, Morrell MR, Moore CA, Shigemura N, Zeevi A, McDyer JF, Venkataramanan R. Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients. Am J Transplant 2018; 18:1527-1533. [PMID: 29513387 DOI: 10.1111/ajt.14723] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/16/2018] [Accepted: 02/20/2018] [Indexed: 02/06/2023]
Abstract
Calcineurin inhibitors (CNIs) are the backbone of traditional immunosuppressive regimens for lung transplant recipients (LTR). The CNIs are both narrow therapeutic index drugs with significant interpatient and intrapatient variability that require therapeutic drug monitoring to ensure safety and effectiveness. We hypothesized that tacrolimus time-in-therapeutic range (TTR) affects acute and chronic rejection rates in LTRs. This was a single-center, observational, cross-sectional study of 292 adult LTRs. Subjects who received tacrolimus posttransplant for the first year were included. TTR was calculated at 1 year using protocol goal ranges (12-15 mg/mL months 0-6; 10-12 mg/mL for months 7-12). The primary outcome was acute cellular rejection (ACR) burden at 1 year. Chronic lung allograft dysfunction (CLAD), mortality, and infection rate were assessed as secondary outcomes at 1 year. Primary and secondary outcomes were assessed using logistic regression. Increasing TTR by 10% was associated with a significantly lower likelihood of high-burden ACR at 1 year on univariable (OR 0.46, 95% CI 0.40-0.54, P < .001) and multivariable (OR 0.64, 95% CI 0.47-0.86, P = .003) assessment, controlling for age and induction agent. Increasing TTR by 10% was also associated with lower rates of CLAD (P < .001) and mortality (P < .001) at 1 year. Prospective studies confirming these findings appear warranted.
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Affiliation(s)
- Christopher R Ensor
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.,Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Carlo J Iasella
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
| | - Kate M Harrigan
- Department of Pharmacy Systems, Outcomes & Policy, University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA
| | - Matthew R Morrell
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Cody A Moore
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Norihisa Shigemura
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Adriana Zeevi
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - John F McDyer
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.,Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Sablik KA, Clahsen-van Groningen MC, Hesselink DA, van Gelder T, Betjes MGH. Tacrolimus intra-patient variability is not associated with chronic active antibody mediated rejection. PLoS One 2018; 13:e0196552. [PMID: 29746495 PMCID: PMC5944964 DOI: 10.1371/journal.pone.0196552] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 04/16/2018] [Indexed: 01/14/2023] Open
Abstract
Background Chronic active antibody mediated rejection (c-aABMR) is a major cause of long-term kidney allograft loss. It is hypothesized that frequent sub-therapeutic exposure to immunosuppressive drugs, in particular tacrolimus (Tac), is a risk factor for the development of c-aABMR. The intra-patient variability (IPV) in Tac exposure may serve as a substitute biomarker for underexposure and/or non-adherence. In this study, the association between Tac IPV and the development of c-aABMR was investigated. Methods We retrospectively included 59 patients diagnosed with c-aABMR and compared them to 189 control patients matched for age, year of transplantation and type of kidney donor. The Tac IPV was calculated from pre-dose tacrolimus concentrations measured over a 3 year period preceding the diagnosis of c-aABMR. The mean Tac predose concentrations (C0), Tac IPV, renal allograft function and graft survival were compared between the groups. Results Tac IPV was 24.4% for the cases versus 23.6% for the controls (p = 0.47). The mean Tac C0 was comparable for the cases (5.8 ng/mL) and control patients (6.1 ng/mL, p = 0.08). Only in the c-aABMR group a significant decline in both mean Tac C0 and allograft function over the timespan of 3 years was observed (p = 0.03 and p<0.001). Additionally, in the group of c-aABMR patients a high IPV was associated with inferior graft survival (p = 0.03). Conclusions A high Tac IPV per se does not predispose to the development of c-aABMR but is associated with inferior graft survival once c-aABMR is diagnosed.
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Affiliation(s)
- Kasia A. Sablik
- Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- * E-mail:
| | | | - Dennis A. Hesselink
- Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Teun van Gelder
- Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Michiel G. H. Betjes
- Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Andrews LM, Li Y, De Winter BCM, Shi YY, Baan CC, Van Gelder T, Hesselink DA. Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients. Expert Opin Drug Metab Toxicol 2017; 13:1225-1236. [PMID: 29084469 DOI: 10.1080/17425255.2017.1395413] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren't sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don't necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure - research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice.
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Affiliation(s)
- Louise M Andrews
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Yi Li
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.,b Department of Laboratory Medicine , West China Hospital of Sichuan University , Chengdu , China
| | - Brenda C M De Winter
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Yun-Ying Shi
- c Department of Nephrology , West China Hospital of Sichuan University , Chengdu , China
| | - Carla C Baan
- d Department of Internal Medicine , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Teun Van Gelder
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.,d Department of Internal Medicine , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Dennis A Hesselink
- d Department of Internal Medicine , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
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Vanhove T, Vermeulen T, Annaert P, Lerut E, Kuypers DRJ. High Intrapatient Variability of Tacrolimus Concentrations Predicts Accelerated Progression of Chronic Histologic Lesions in Renal Recipients. Am J Transplant 2016; 16:2954-2963. [PMID: 27013142 DOI: 10.1111/ajt.13803] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 03/17/2016] [Accepted: 03/19/2016] [Indexed: 01/25/2023]
Abstract
High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6-12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09-5.60, p = 0.031; and OR 2.40, 95% CI 1.03-5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.
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Affiliation(s)
- T Vanhove
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - T Vermeulen
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - P Annaert
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, Leuven, Belgium
| | - E Lerut
- Department of Imaging and Pathology, KU Leuven - University of Leuven, and Department of Pathology, University Hospitals Leuven, Leuven, Belgium
| | - D R J Kuypers
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
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