Backgrounds: Tacrolimus is available as an immediate-release, twice-daily formulation (Tac-BID), and a prolonged-release once-daily formulation (Tac-QD). A number of studies found that the daily dose was higher for Tac-QD than Tac-BID to achieve a similar trough level (C0). Patients with the CYP3A5*1 allele (CYP3A5 expressers) require a higher daily tacrolimus dose than those with the CYP3A5*3/*3 genotype (non-expressers) in order to maintain C0. The present study compares pharmacokinetics and CYP3A5 pharmacogenetics between Tac-BID and Tac-QD from the first dosing day (pre-transplantation) to 1-year post-transplantation, and its impact on clinical outcome.
Methods: The 24-h pharmacokinetics and CYP3A5 6986A>G pharmacogenetics were compared between Tac-QD and Tac-BID at pre-transplantation, and at 1-month and 1-year post-transplantation in 24 de novo renal transplant recipients in each formulation.
Results: The allele frequencies of CYP3A5*1 and 3 were 27.1% and 72.9% in each group. The dose-adjusted C0 and AUC0-24 of tacrolimus increased approximately two-fold from pre-transplantation to 1-year post-transplantation. Although there were good correlations between AUC0-24 and C0 for both formulations, the same C0 value achieved higher calculated AUC0-24 for Tac-QD than Tac-BID at all 3 time points. In patients with the CYP3A5*1 allele (CYP3A5 expressers), the dose-adjusted C0 and AUC0-24 were approximately 45% and 25%, respectively, lower for Tac-QD than Tac-BID at all 3 time points. In patients with the CYP3A5*3/*3 genotype (non-expressers), the dose-adjusted C0 was lower for Tac-QD than Tac-BID, but the difference in the dose-adjusted AUC0-24 was not significant. There were no remarkable differences in clinical outcomes between two formulations.
Conclusions: There are time dependent changes of pharmacokinetics and CYP3A5 pharmacogenetics in both formulations. Although its impact on clinical outcome may be minor, take notice that the target C0 achieving the same AUC0-24 may be different between Tac-QD and Tac-BID and between CYP3A5 expressers and non-expressers.
To cite this abstract in AMA style:Satoh S, Niioka T, Kagaya H, Numakura K, Saito M, Inoue T, Komine N, Akihama S, Narita S, Tsuchiya N, Habuchi T, Miura M. Pharmacokinetics and CYP3A5 Pharmacogenetics for Once- Versus Twice-Daily Tacrolimus from First Dosing Day to 1 Year Post-Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/pharmacokinetics-and-cyp3a5-pharmacogenetics-for-once-versus-twice-daily-tacrolimus-from-first-dosing-day-to-1-year-post-transplantation/. Accessed January 25, 2021.
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