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

Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.