RESUMO
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.
Assuntos
Transplante de Rim , Tacrolimo/farmacocinética , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Biomarcadores Farmacológicos/análise , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Feminino , Genótipo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Masculino , México , Pessoa de Meia-Idade , Modelos Biológicos , Farmacogenética , Polimorfismo Genético , Tacrolimo/administração & dosagem , Adulto JovemRESUMO
INTRODUCTION: In April 1991 was performed the first kidney transplant at the Hospital Central Dr. Ignacio Morones Prieto. In August 1999, formally started the kidney transplant program. OBJECTIVE: To describe the experience in kidney transplant at HCIMP. MATERIALS AND METHODS: Retrospective cohort study, which includes all kidney transplants performed during the period August 1999 to June 2011. We excluded patients whose medical record was eliminated or with incomplete data for analysis. It describes the general characteristics of kidney transplant recipients, transplant-related variables, initial immunosuppression and complications. The survival analysis was performed using the Kaplan-Meier method. The curves were compared using the log-rank test. RESULTS: From August 1999 to June 2011 were performed 517 kidney transplants at Central Hospital, of which 411 patients were analyzed. Ten years overall graft-survival was 73%. Both, the history of infection or acute rejection were associated with lower graft survival. The main cause of death, in our population, was infectious processes. CONCLUSION: Graft survival at 10 years was 73%, which is similar to that reported in the literature. A history of acute rejection and infection are factors associated with lower survival.