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.

Trial registration: ClinicalTrials.gov NCT00772148.

Keywords: acute rejection; calcineurin inhibitor; immunosuppression; phase II; safety.

Conflict of interest statement

K.U. receives honoraria from Veloxis Pharmaceuticals, Inc. and Astellas Pharma US, Inc. for serving on speakers' bureaus. A.S. receives honoraria from Veloxis Pharmaceuticals, Inc. for service on their speakers' bureau. A.E.A. receives honoraria from Eisai and Bayer for consulting on advisory boards, and from Bayer and Novartis for serving on speakers' bureaus. C.T. and D.R.S. received their standard salary from Veloxis Pharmaceuticals, Inc. during their work on the manuscript. D.A.D., W.C., and L. T. declare that they have no conflicts of interest to disclose.

© 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Subject disposition.

Figure 2

24‐hour arithmetic mean whole blood tacrolimus concentrations (ng/mL) and SD on days 1, 7, and 14 for LCPT and IR‐Tac. All BLQ values entered as zero and included as such in the calculation of means. BLQ, below limit of quantification; IR‐Tac, twice‐daily immediate‐release tacrolimus capsules; LCPT, once‐daily extended‐release tablet formulation of tacrolimus; SD, standard deviation.

Figure 3

24‐hour arithmetic mean whole blood tacrolimus concentrations (ng/mL) and SD on days 1, 7, and 14 for LCPT and IR‐Tac, exposure normalized.* All BLQ values entered as zero and included as such in the calculation of means. BLQ, below limit of quantification; IR‐Tac, twice‐daily immediate‐release tacrolimus capsules; LCPT, once‐daily extended‐release tablet formulation of tacrolimus; SD, standard deviation. *Exposure normalization is an adjustment by which the AUC of LCPT and IR‐Tac are made equal, and all other pharmacokinetic parameters mathematically adjusted, to allow direct comparisons of pharmacokinetic parameters under assumption of equivalent exposure.

Figure 4

Correlation between dose‐normalized AUC0–24h and Cmin on day 7 for LCPT and IR‐Tac. IR‐Tac, twice‐daily immediate‐release tacrolimus capsules; LCPT, once‐daily extended‐release tablet formulation of tacrolimus.

Figure 5

Correlation between dose‐normalized AUC0–24h and Cmin on day 14 for LCPT and IR‐Tac. IR‐Tac, twice‐daily immediate‐release tacrolimus capsules; LCPT, once‐daily extended‐release tablet formulation of tacrolimus.