Limited Sampling Strategies Fail to Accurately Predict Mycophenolic Acid Area Under the Curve in Kidney Transplant Recipients and the Impact of Enterohepatic Recirculation.
Journal
Therapeutic drug monitoring
ISSN: 1536-3694
Titre abrégé: Ther Drug Monit
Pays: United States
ID NLM: 7909660
Informations de publication
Date de publication:
23 Jul 2024
23 Jul 2024
Historique:
received:
25
04
2024
accepted:
16
06
2024
medline:
26
7
2024
pubmed:
26
7
2024
entrez:
24
7
2024
Statut:
aheadofprint
Résumé
Therapeutic drug monitoring for mycophenolic acid (MPA) is challenging due to difficulties in measuring the area under the curve (AUC). Limited sampling strategies (LSSs) have been developed for MPA therapeutic drug monitoring but come with risk of unacceptable performance. The authors hypothesized that the poor predictive performance of LSSs were due to the variability in MPA enterohepatic recirculation (EHR). This study is the first to evaluate LSSs models performance in the context of EHR. Adult kidney transplant recipients (n = 84) receiving oral mycophenolate mofetil underwent intensive MPA pharmacokinetic sampling. MPA AUC0-12hr and EHR were determined. Published MPA LSSs in kidney transplant recipients receiving tacrolimus were evaluated for their predictive performance in estimating AUC0-12hr in our full cohort and separately in individuals with high and low EHR. None of the evaluated LSS models (n = 12) showed good precision or accuracy in predicting MPA AUC0-12hr in the full cohort. In the high EHR group, models with late timepoints had better accuracy but low precision, except for 1 model with late timepoints at 6 and 10 hours postdose, which had marginally acceptable precision. For all models, the good guess of predicted AUC0-12hr (±15% of observed AUC0-12hr) was highly variable (range, full cohort = 19%-61.9%; high EHR = 4.5%-65.9%; low EHR = 27.5%-62.5%). The predictive performance of the LSS models varied according to EHR status. Timepoints ≥5 hours postdose in LSS models are essential to capture EHR. Models and strategies that incorporate EHR during development are required to accurately ascertain MPA exposure.
Sections du résumé
BACKGROUND
BACKGROUND
Therapeutic drug monitoring for mycophenolic acid (MPA) is challenging due to difficulties in measuring the area under the curve (AUC). Limited sampling strategies (LSSs) have been developed for MPA therapeutic drug monitoring but come with risk of unacceptable performance. The authors hypothesized that the poor predictive performance of LSSs were due to the variability in MPA enterohepatic recirculation (EHR). This study is the first to evaluate LSSs models performance in the context of EHR.
METHODS
METHODS
Adult kidney transplant recipients (n = 84) receiving oral mycophenolate mofetil underwent intensive MPA pharmacokinetic sampling. MPA AUC0-12hr and EHR were determined. Published MPA LSSs in kidney transplant recipients receiving tacrolimus were evaluated for their predictive performance in estimating AUC0-12hr in our full cohort and separately in individuals with high and low EHR.
RESULTS
RESULTS
None of the evaluated LSS models (n = 12) showed good precision or accuracy in predicting MPA AUC0-12hr in the full cohort. In the high EHR group, models with late timepoints had better accuracy but low precision, except for 1 model with late timepoints at 6 and 10 hours postdose, which had marginally acceptable precision. For all models, the good guess of predicted AUC0-12hr (±15% of observed AUC0-12hr) was highly variable (range, full cohort = 19%-61.9%; high EHR = 4.5%-65.9%; low EHR = 27.5%-62.5%).
CONCLUSIONS
CONCLUSIONS
The predictive performance of the LSS models varied according to EHR status. Timepoints ≥5 hours postdose in LSS models are essential to capture EHR. Models and strategies that incorporate EHR during development are required to accurately ascertain MPA exposure.
Identifiants
pubmed: 39047238
doi: 10.1097/FTD.0000000000001248
pii: 00007691-990000000-00253
doi:
Banques de données
ClinicalTrials.gov
['NCT04953715']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
Lentine KL, Smith JM, Miller JM, et al. OPTN/SRTR 2021 annual data report: kidney. Am J Transpl. 2023;23:S21–S120.
Lee WA, Gu L, Miksztal AR, et al. Bioavailability improvement of mycophenolic acid through amino ester derivatization. Pharm Res. 1990;7:161–166.
Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46:13–58.
Colom H, Lloberas N, Andreu F, et al. Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients. Kidney Int. 2014;85:1434–1443.
Shaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transpl. 2003;3:534–542.
Shaw LM, Korecka M, Aradhye S, et al. Mycophenolic acid area under the curve values in African American and caucasian renal transplant patients are comparable. J Clin Pharmacol. 2000;40:624–633.
Bergan S, Brunet M, Hesselink DA, et al. Personalized therapy for mycophenolate: consensus report by the international association of therapeutic drug monitoring and clinical toxicology. Ther Drug Monit. 2021;43:150–200.
De Winter BCM, Mathot RAA, Sombogaard F, et al. Nonlinear relationship between mycophenolate mofetil dose and mycophenolic acid exposure: implications for therapeutic drug monitoring. Clin J Am Soc Nephrol. 2011;6:656–663.
Knight SR, Morris PJ. Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical practice? A systematic review. Transplantation. 2008;85:1675–1685.
Le Meur Y, Borrows R, Pescovitz MD, et al. Therapeutic drug monitoring of mycophenolates in kidney transplantation: report of the transplantation society consensus meeting. Transpl Rev. 2011;25:58–64.
Van Gelder T, Silva HT, De Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008;86:1043–1051.
Gaston RS, Kaplan B, Shah T, et al. Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the opticept trial. Am J Transpl. 2009;9:1607–1619.
Le Meur Y, Büchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transpl. 2007;7:2496–2503.
Barraclough KA, Isbel NM, Staatz CE. Evaluation of the mycophenolic acid exposure estimation methods used in the APOMYGERE, FDCC, and opticept trials. Transplantation. 2010;90:44–51.
Ting LSL, Villeneuve E, Ensom MHH. Beyond cyclosporine: a systematic review of limited sampling strategies for other immunosuppressants. Ther Drug Monit. 2006;28:419–430.
Van Der Meer AF, Marcus MAE, Touw DJ, et al. Optimal sampling strategy development methodology using maximum a posteriori bayesian estimation. Ther Drug Monit. 2011;33:133–146.
Kiang TKL, Ensom MHH. Therapeutic drug monitoring of mycophenolate in adult solid organ transplant patients: an update. Expert Opin Drug Metab Toxicol. 2016;12:545–553.
Sobiak J, Resztak M. A systematic review of multiple linear regression-based limited sampling strategies for mycophenolic acid area under the concentration–time curve estimation. Eur J Drug Metab Pharmacokinet. 2021;46:721–742.
Okour M, Jacobson PA, Ahmed MA, et al. Mycophenolic acid and its metabolites in kidney transplant recipients: a semimechanistic enterohepatic circulation model to improve estimating exposure. J Clin Pharmacol. 2018;58:628–639.
Pescovitz MD, Vincenti F, Hart M, et al. Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients. Br J Clin Pharmacol. 2007;64:758–771.
Cattaneo D, Merlini S, Zenoni S, et al. Influence of Co‐medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transpl. 2005;5:2937–2944.
Liu Y, Zhang H, Li J, et al. Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: exploratory analysis of the effects of clinical factors and gene variants. Basic Clin Pharmacol Toxicol. 2022;131:60–73.
Mino Y, Naito T, Matsushita T, et al. Comparison of pharmacokinetics of mycophenolic acid and its glucuronide between patients with lupus nephritis and with kidney transplantation. Ther Drug Monit. 2008;30:656–661.
Naito T, Mino Y, Otsuka A, et al. Impact of calcineurin inhibitors on urinary excretion of mycophenolic acid and its glucuronide in kidney transplant recipients. J Clin Pharmacol. 2009;49:710–718.
Miura M, Satoh S, Niioka T, et al. Early phase limited sampling strategy characterizing tacrolimus and mycophenolic acid pharmacokinetics adapted to the maintenance phase of renal transplant patients. Ther Drug Monit. 2009;31:467–474.
Uchiyama K, Saito Y, Takekuma Y, et al. Pharmacokinetics of mycophenolic acid after haplo-hematopoietic stem cell transplantation in Japanese recipients. J Oncol Pharm Pract. 2022;28:31–38.
Tornatore KM, Attwood K, Venuto RC, et al. Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable black and white kidney transplant recipients: implications for Health inequities. Clin Transl Sci. 2023;16:861–871.
Chaabane A, Aouam K, Fredj NBen, et al. Limited sampling strategy of mycophenolic acid in adult kidney transplant recipients: influence of the post-transplant period and the pharmacokinetic profile. J Clin Pharmacol. 2013;53:925–933.
Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385:1737–1749.
Pawinski T, Hale M, Korecka M, et al. Limited sampling strategy for the estimation of mycophenolic acid area under the curve in adult renal transplant patients treated with concomitant tacrolimus. Clin Chem. 2002;48:1497–1504.
Kuriata-Kordek M, Boratynska M, Falkiewicz K, et al. The Influence of Calcineurin Inhibitors on Mycophenolic Acid Pharmacokinetics. Transplant Proc. 2003;35:2369–2371.
Toda T, Watanabe H, Kurosawa N, et al. Limited sampling strategy for estimating area under the concentration curve for mycophenolic acid in renal transplant recipients with Co-administration of tacrolimus. Iryo Yakugaku (Japanese J Pharm Health Care Sciences). 2004;30:1–7.
Teshima D, Maiguma T, Kaji H, et al. Estimation of the area under the curve for mycophenolic acid in adult renal transplant patients with concomitant tacrolimus using a limited sampling strategy. J Clin Pharm Ther. 2008;33(2):159–163.
Miura M, Satoh S, Niioka T, et al. Limited sampling strategy for simultaneous estimation of the area under the concentration-time curve of tacrolimus and mycophenolic acid in adult renal transplant recipients. Ther Drug Monit. 2008;30:52–59.
Poulin E, Greanya ED, Partovi N, et al. Development and validation of limited sampling strategies for tacrolimus and mycophenolate in steroid-free renal transplant regimens. Ther Drug Monit. 2011;33:50–55.
Barraclough KA, Isbel NM, Johnson DW, et al. A limited sampling strategy for the simultaneous estimation of tacrolimus, mycophenolic acid and unbound prednisolone exposure in adult kidney transplant recipients. Nephrology. 2012;17:294–299.
Cai W, Ye C, Sun X, et al. Limited sampling strategy for predicting area under the concentration-time curve for mycophenolic acid in Chinese adults receiving mycophenolate mofetil and tacrolimus early after renal transplantation. Ther Drug Monit. 2015;37:304–310.
Cai W, Cai Q, Xiong N, et al. Limited sampling strategy for estimating mycophenolic acid exposure on day 7 post-transplant for two mycophenolate Mofetil formulations derived from 20 Chinese renal transplant recipients. Transplant Proc. 2018;50:1298–1304.
Hulin A, Blanchet B, Audard V, et al. Comparison of 3 estimation methods of mycophenolic acid auc based on a limited sampling strategy in renal transplant patients. Ther Drug Monit. 2009;31:224–232.
Musuamba FT, Mourad M, Haufroid V, et al. Statistical tools for dose individualization of mycophenolic acid and tacrolimus Co-administered during the first month after renal transplantation. Br J Clin Pharmacol. 2013;75:1277–1288.
Wang P, Xie H, Zhang Q, et al. Population pharmacokinetics of mycophenolic acid in renal transplant patients: a comparison of the early and stable posttransplant stages. Front Pharmacol. 2022;13:859351.
Shao K, Jia Y, Lu J, et al. Estimation of mycophenolic acid exposure in Chinese renal transplant patients by a joint deep learning model. Ther Drug Monit. 2022;44:738–746.
ABIS 3.0 - Limoges University Hospital. Accessed June 8, 2024.
Prémaud A, Le Meur Y, Debord J, et al. Maximum a posteriori Bayesian estimation of mycophenolic acid pharmacokinetics in renal transplant recipients at different postgrafting periods. Ther Drug Monit. 2005;27:354–361.
Barraclough KA, Isbel NM, Franklin ME, et al. Evaluation of limited sampling strategies for mycophenolic acid after mycophenolate mofetil intake in adult kidney transplant recipients. Ther Drug Monit. 2010;32:723–733.
Bruchet NK, Ensom MHH. Limited sampling strategies for mycophenolic acid in solid organ transplantation: a systematic review. Expert Opin Drug Metab Toxicol. 2009;5:1079–1097.
Na Takuathung M, Sakuludomkan W, Koonrungsesomboon N. The impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of mycophenolic acid: systematic review and meta-analysis. Clin Pharmacokinet. 2021;60:1291–1302.
Dasgupta A. Therapeutic drug monitoring of mycophenolic acid. Adv Clin Chem. 2016;76:165–184.