A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach

Background Single nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes have been reported to be an important cause of variability in the pharmacokinetics of tacrolimus in renal transplant patients. The aim of this study was to merge all of the new genetic information available with tacrolimus pharmacokinetics to generate a more robust population model with data from renal transplant recipients. Methods Tacrolimus exposure data from 304 renal transplant recipients were collected throughout the first year after transplantation and were simultaneously analyzed with a population pharmacokinetic approach using NONMEMA (R) version 7.2. Results The tacrolimus whole-blood concentration versus time data were best described by a two-open-compartment model with inter-occasion variability assigned to plasma clearance. The following factors led to the final model, which significantly decreased the minimum objective function value (p < 0.001): a new genotype cluster variable combining the CYP3A5*3 and CYP3A4*22 SNPs defined as extensive, intermediate, and poor metabolizers; the standardization of tacrolimus whole blood concentrations to a hematocrit value of 45%; and age included as patients < 63 years versus patients >= 63 years. External validation confirmed the prediction ability of the model with median bias and precision values of 1.17 ng/mL (95% confidence interval [CI] -3.68 to 4.50) and 1.64 ng/mL (95% CI 0.11-5.50), respectively. Simulations showed that, for a given age and hematocrit at the same fixed dose, extensive metabolizers required the highest doses followed by intermediate metabolizers and then poor metabolizers. Conclusions Tacrolimus disposition in renal transplant recipients was described using a new population pharmacokinetic model that included the CYP3A5*3 and CYP3A4*22 genotype, age, and hematocrit.