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

Clin Pharmacol Ther. 2004 Dec;76(6):545-56. doi: 10.1016/j.clpt.2004.08.022.

Abstract

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 genotyped 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.

MeSH terms

  • Adult
  • Algorithms
  • Alleles
  • Bayes Theorem
  • Cyclosporine / pharmacokinetics*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA / genetics
  • DNA / isolation & purification
  • Ethnic Groups
  • Female
  • Genes, MDR / genetics*
  • Heart Transplantation / physiology*
  • Humans
  • Immunosuppressive Agents / pharmacokinetics*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Kidney Transplantation / physiology*
  • Male
  • Middle Aged
  • Nonlinear Dynamics
  • Polymorphism, Single Nucleotide / genetics
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Immunosuppressive Agents
  • Isoenzymes
  • Cyclosporine
  • DNA
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human