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

• Published in: British journal of clinical pharmacology Vol. 85; no. 8; pp. 1692 - 1703
• Main Authors: Lu, Zheng, Bonate, Peter, Keirns, James
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.08.2019
• Subjects: Adult; African Continental Ancestry Group - statistics & numerical data; Asian Continental Ancestry Group - statistics & numerical data; Biological Availability; Biological Variation, Population - ethnology; Clinical Trials, Phase II as Topic; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - pharmacokinetics; Drug Administration Schedule; European Continental Ancestry Group - statistics & numerical data; Female; Graft Rejection - immunology; Graft Rejection - prevention & control; Heart Transplantation - adverse effects; Humans; immunosuppression; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Kidney Transplantation - adverse effects; Liver Transplantation - adverse effects; Male; Middle Aged; Models, Biological; NONMEM; Original; pharmacokinetics; Tacrolimus - administration & dosage; Tacrolimus - pharmacokinetics; Transplant Recipients - statistics & numerical data; transplantation; Young Adult; pharmacokinetics; immunosuppression; transplantation; NONMEM
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13952

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.