Jeremiah D Momper, Raman Venkataramanan, Arin S Jantz, Diane M Cibrik, Kelly Birdwell, Tk Nguyen, Brian M Masters, Samir J Patel
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Abstract
Background: For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac).
Methods: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile.
Results: The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively.
Conclusions: Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.
期刊介绍：
Therapeutic Drug Monitoring is a peer-reviewed, multidisciplinary journal directed to an audience of pharmacologists, clinical chemists, laboratorians, pharmacists, drug researchers and toxicologists. It fosters the exchange of knowledge among the various disciplines–clinical pharmacology, pathology, toxicology, analytical chemistry–that share a common interest in Therapeutic Drug Monitoring. The journal presents studies detailing the various factors that affect the rate and extent drugs are absorbed, metabolized, and excreted. Regular features include review articles on specific classes of drugs, original articles, case reports, technical notes, and continuing education articles.
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