Dataset Information

Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.

ABSTRACT: The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.

SUBMITTER: DuBay DA

PROVIDER: S-EPMC6899533 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.

DuBay Derek A DA Teperman Lewis L Ueda Kimi K Silverman Andrew A Chapman William W Alsina Angel E AE Tyler Carmelina C Stevens Daniel R DR

Clinical pharmacology in drug development 20190122 8

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentr ...[more]

PMID: 30667591

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Project description:BACKGROUND:Tacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD. METHODS:A cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA. RESULTS:Conversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p?=?0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort. CONCLUSIONS:The CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements. TRIAL REGISTRATION:Clinical trials.gov identifier: NCT01884480.

Project description:INTRODUCTION:Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS:This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n?=?37) or PR-Tac 0.20 mg/kg/day (n?=?38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS:PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n?=?33; PR-Tac, n?=?35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with?<?12% in each group having below-target trough levels over the study period. LCPT demonstrated?~?30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p?=?0.007); day 7, 1.25 (p?=?0.051); day 14, 1.43 (p?=?0.002)] and?~?30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p?<?0.001); day 7, 0.68 (p?<?0.001); day 14, 0.73 (p?=?0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~?40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION:In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION:Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING:Chiesi Farmaceutici S.p.A.

Dataset Information

Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.

Publications

Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.

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