Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2004-12

AUTHORS

Dennis A. Hesselink, Teun Gelder, Ron H. N. Schaik, Aggie H. M. M. Balk, Ilse P. Heiden, Thea Dam, Marloes Werf, Willem Weimar, Ron A. A. Mathot

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. More... »

PAGES

545-556

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1016/j.clpt.2004.08.022

DOI

http://dx.doi.org/10.1016/j.clpt.2004.08.022

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1040190410

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15592326


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