Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic-polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes

Objective: Our objective was to determine the relationship between single nucleotide polymorphisms (SNPs) in the multidrug resistance 1 (MDR-1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 and the pharmacokinetics of cyclosporine (INN, ciclosporin). Methods: Cyclosporine pharmacokinetics of 151 kidney and heart transplant recipients undergoing maintenance therapy was described by use of nonlinear mixed-effects modeling (NONMEM) according to a 2-compartment pharmacokinetic model with first-order absorption and elimination. All patients were geno-typed for the CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 3435C-->T SNPs. Results: For a typical 70-kg white patient, the following parameters were estimated: absorption rate constant, 1.27 h(-1); absorption time lag, 0.47 hour; oral volume of distribution of the central and peripheral compartment, 56.3 and 185.0 L, respectively; oral clearance (Cl/F), 30.7 L/h; and oral intercompartmental clearance, 31.7 L/h. Estimated interpatient variability of Cl/F was 28%. Cl/F was significantly correlated with weight and ethnicity; Cl/F was 13% higher (95% confidence interval, 8%-18%; P <.005) in white patients than in black and Asian patients. In carriers of a CYP3A4*1B variant allele, Cl/F was 9% (95% confidence interval, 1%-17%; P <.05) higher compared with CYP3A4*1 homozygotes, and this effect was independent of ethnicity or weight. Incorporation of these covariates into the NONMEM model did not markedly reduce interpatient variability of Cl/F. None of the other SNPs studied significantly influenced any of the pharmacokinetic parameters. Conclusion: Patients carrying a CYP3A4*1B variant allele have a significantly higher oral cyclosporine clearance compared with patients homozygous for CYP3A4*1. However, this genetic effect on cyclosporine disposition was small, and genotyping of transplant recipients for CYP3A4 is thus unlikely to assist in planning initial cyclosporine dosing.