Dosing recommendations based on population pharmacokinetics of tacrolimus in Mexican adult patients with kidney transplant

• Published in: Basic & clinical pharmacology & toxicology 2019-03, Vol.124 (3), p.303-311
• Main Authors: Reséndiz‐Galván, Juan Eduardo, Medellín‐Garibay, Susanna Edith, Milán‐Segovia, Rosa del Carmen, Niño‐Moreno, Perla del Carmen, Isordia‐Segovia, Javier, Romano‐Moreno, Silvia
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Bioavailability; Biological Availability; Biomarkers, Pharmacological - analysis; Computer simulation; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Dosage; Female; Formulations; Genotype; Hematocrit; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Kidney Transplantation; Kidneys; Male; Mexico; Middle Aged; Models, Biological; Patients; Pharmacogenetics; Pharmacokinetics; Pharmacology; Polymorphism, Genetic; Population; population pharmacokinetics; Population studies; renal transplantation; Stability analysis; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - pharmacokinetics; Young Adult
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.13138

The aim of this study was to perform a population pharmacokinetic analysis of tacrolimus in Mexican adult kidney transplant patients to analyse the influence of clinical and genetic covariates to propose a dosage regimen. Kidney transplant patients (>18 years old) receiving oral tacrolimus treatment were included in the current study. The population pharmacokinetic model was built using a one‐compartment model and the First Order Conditional Estimation method with Interaction (FOCEI via NONMEM v.7.3.). A total of 600 tacrolimus trough blood concentrations from 52 kidney transplant patients were analysed. Tacrolimus clearances were 26, 18.8 and 12.3 L/h, for patients with genetic polymorphisms CYP3A5*1*1, *1*3 and *3*3, respectively. The influence of haematocrit was inversely related to tacrolimus clearance, following an allometric power function. Total volume of distribution was 604 L. Interindividual variability associated with tacrolimus clearance and distribution volume for the final model was 33 and 63%, respectively, with a residual error of 2.5 ng/mL. Relative bioavailability was calculated between generic formulations A (0.53) and B (1) of tacrolimus. Internal validation was performed through bootstrap analysis to evaluate the stability of the final model; external validation was performed in a new group of patients (n = 13) to estimate residual errors on basic (57.8%) and final (34.8%) models. Finally, stochastic simulations were performed to propose a dosage regimen based on haematocrit, CYP3A5 genotype and generic formulation of tacrolimus. A stable and predictive population pharmacokinetic model of tacrolimus was developed for Mexican adult kidney transplant patients; additionally, the proposed dosage regimen of tacrolimus should be prospectively validated.