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Population pharmacokinetics of immediate‐ and prolonged‐release tacrolimus formulations in liver, kidney and heart transplant recipients

Article date: August 2019

By: Zheng Lu, Peter Bonate, James Keirns in Volume 85, Issue 8, pages 1692-1703


Develop a population pharmacokinetics model of tacrolimus in organ transplant recipients receiving twice‐daily, immediate‐release (IR‐T; Prograf) and/or once‐daily, prolonged‐release (PR‐T; Advagraf or Astagraf XL) tacrolimus.


Tacrolimus concentration–time profiles were analysed from 8 Phase II studies in adult and paediatric liver, kidney and heart transplant patients receiving IR‐T and/or PR‐T. A tacrolimus population pharmacokinetic model, including identification of significant covariates, was developed using NONMEM.


Overall, 23,176 tacrolimus concentration records were obtained from 408 patients. A 2‐compartment model with first‐order absorption and elimination described the concentration–time profiles. Tacrolimus absorption rate was 50% slower with PR‐T vs IR‐T. Tacrolimus apparent oral clearance was 44.3 L/h in Whites and 59% higher in Asians. Tacrolimus central volume of distribution was 108 L in males and 55% lower in females; trough concentrations were similar between formulations. Tacrolimus relative bioavailability was similar between formulations (geometric mean ratio PR‐T:IR‐T 95%, 90% confidence intervals: 89%, 101%). Asians had 83% and 51% higher relative bioavailability than Whites and Blacks, respectively, for IR‐T and PR‐T. Whites had 49% and 77% higher relative bioavailability than Blacks for PR‐T and IR‐T, respectively. Blacks had 52% lower relative bioavailability than Whites and Asians for IR‐T and PR‐T. Type of organ transplanted and patient population (adult/paediatric) did not have a significant effect on tacrolimus pharmacokinetics.


This population pharmacokinetic model described data from transplant recipients who received IR‐T and/or PR‐T. Tacrolimus trough concentrations and relative bioavailability were similar between formulations, supporting 1 mg:1 mg conversion from Prograf to Advagraf/Astagraf XL in clinical practice.

DOI: 10.1111/bcp.13952

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