A Population Pharmacokinetic Model and Dosing Algorithm to Guide the Tacrolimus Starting and Follow-Up Dose in Living and Deceased Donor Kidney Transplant Recipients

Clinical Pharmacokinetics, vol. 64, pp. 1379–1394

Abstract

INTRODUCTION: Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to predict an individual's dose requirement following living and deceased donor kidney transplantation. METHODS: In this international, multicenter, retrospective study, data was collected from patients who had received a living or a deceased donor kidney and received tacrolimus twice daily. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). RESULTS: This study included 13,427 tacrolimus concentrations from 1180 kidney transplant recipients. A two-compartment model with first-order absorption best described the data. The mean absorption rate was 6.59/h, apparent clearance 20.7 L/h, central volume of distribution 705 L, and peripheral volume of distribution 7670 L. Higher age, creatinine, and hematocrit, as well as lower height, were associated with lower tacrolimus clearance. Tacrolimus clearance was higher for cytochrome P450 (CYP) 3A5*1 carriers compared with CYP3A5*3/*3 individuals, and lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients. Together, these covariates explained 19.3% of the inter-individual variability in clearance. From the full model, a starting dose algorithm was developed with age, height, and the CYP3A4 and CYP3A5 genotypes as covariates. Both the full model and the starting dose algorithm were successfully internally validated. CONCLUSIONS: In this international, multicenter study, age, CYP3A4 and CYP3A5 genotype, creatinine, height, and hematocrit were identified as significant covariates associated with tacrolimus pharmacokinetics, and can be used to predict the optimal individual's dose requirement for both living and deceased donor kidney transplant recipients.

Authors 11

1. Marith I. Francke corresponding

   Erasmus MC · Erasmus MC Transplant Institute

   Affiliation as printed

   Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center, Room Rg-527, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. m.francke@erasmusmc.nl

   Erasmus MC Transplant Institute, Rotterdam, The Netherlands. m.francke@erasmusmc.nl

   Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands. m.francke@erasmusmc.nl

2. Sebastiaan D. T. Sassen

   Erasmus MC

   Affiliation as printed

   Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

   Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands

3. Núria Lloberas

   Bellvitge University Hospital · Institut d'Investigació Biomédica de Bellvitge

   Affiliation as printed

   Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain

4. Helena Colom

   Universitat de Barcelona

   Affiliation as printed

   Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain

5. Laure Elens

   UCLouvain

   Affiliation as printed

   Integrated PharmacoMetrics, pharmacoGenomics and Pharmacokinetics (PMGK) Research group, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium

   Louvain centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium

6. Serge Moudio

   UCLouvain

   Affiliation as printed

   Integrated PharmacoMetrics, pharmacoGenomics and Pharmacokinetics (PMGK) Research group, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium

   Louvain centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium

7. Aiko P. J. de Vries Aachen Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

8. Dirk Jan A. R. Moes Aachen Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

9. Ron H. N. van Schaik

   Erasmus MC

   Affiliation as printed

   Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

10. Dennis Alexander Hesselink

    Erasmus MC · Erasmus MC Transplant Institute

    Affiliation as printed

    Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center, Room Rg-527, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Erasmus MC Transplant Institute, Rotterdam, The Netherlands

11. Brenda C. M. de Winter

    Erasmus MC

    Affiliation as printed

    Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands