Pharmacokinetics of prolonged-release tacrolimus versus immediate-release tacrolimus in de novo liver transplantation: A randomized phase III substudy

Clin Transplant. 2017 Jun;31(6). doi: 10.1111/ctr.12958. Epub 2017 Apr 27.


Background: With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses.

Methods: This substudy of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2 mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1 mg/kg/day) during the first 2 weeks post-transplant.

Results: Pharmacokinetic data were analyzed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC0-24 ) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC0-24 (normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC0-24 and concentration at 24 hours after the morning dose (r=.96 and r=.86, respectively), and the slope of the line of best fit was similar for both formulations.

Conclusions: Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. ( number: NCT00189826).

Keywords: calcineurin inhibitor; immunosuppressant; liver transplantation; living donor; pharmacokinetics/pharmacodynamics; rejection; tacrolimus.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Area Under Curve
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Graft Rejection / drug therapy*
  • Graft Rejection / etiology
  • Graft Rejection / metabolism
  • Graft Survival / drug effects*
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacokinetics*
  • Liver Transplantation / adverse effects*
  • Male
  • Middle Aged
  • Postoperative Complications
  • Prognosis
  • Risk Factors
  • Tacrolimus / administration & dosage
  • Tacrolimus / pharmacokinetics*


  • Immunosuppressive Agents
  • Tacrolimus

Associated data