Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the and genes

Abstract

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). 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 genotyped for the CYP3A4*1B and *3 , CYP3A5*3 and *6 , and MDR-1 3435C-->T SNPs. 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. 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.