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

Abstract

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.

Keywords: NONMEM; immunosuppression; pharmacokinetics; transplantation.

Figure 1

Basic goodness‐of‐fit graphs for the final tacrolimus population pharmacokinetics model. A, Observed vs population predicted tacrolimus concentrations. B, Observed vs individual predicted tacrolimus concentrations. C, Observed vs individual predicted tacrolimus concentrations in log scale. D, Conditional weighted residual error vs population predicted tacrolimus concentrations. E, Conditional weighted residual error vs time. F, Individual weighted residual error vs individual predicted tacrolimus concentrations. Note: the solid line in cyan is the line of identity or horizontal line, and the green line is the locally estimated scatterplot smoothing line

Figure 2

Prediction‐corrected visual predictive check graphs based on the final tacrolimus population pharmacokinetics model. The solid red line represents the median observed plasma tacrolimus concentration, and the semi‐transparent red field represents a simulation‐based 95% CI for the median. The observed 5^th and 95^th percentiles are presented with dashed red lines, and the 95% CIs for the corresponding model predicted percentiles are shown as semitransparent blue fields. The observed plasma concentrations are represented by blue circles. CI, confidence interval

Figure 3

Simulated tacrolimus trough concentration for all covariates identified. A, Tacrolimus trough concentration stratified by race (White, Black, Asian), tacrolimus formulation (immediate‐release tacrolimus, prolonged‐release tacrolimus) and sex (male, female). B, Tacrolimus trough concentration stratified by aspartate aminotransferase (normal = 25 IU/L, mild elevation = 100 IU/L, moderate elevation = 400 IU/L), race, sex and tacrolimus formulation. C, Tacrolimus trough concentration stratified by albumin, race, sex and tacrolimus formulation. D, Interpatient variability in tacrolimus trough concentrations (concentration immediately prior to dosing across multiple doses) for immediate‐ and prolonged‐release tacrolimus. The shaded grey area represents the therapeutic window for tacrolimus trough concentrations (5–20 ng/mL). The box, solid line, and whiskers represent the interquartile range, median, and 5^th/95^th percentiles, respectively, of simulated tacrolimus trough concentrations