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 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.


CONCLUSIONS
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.
Hesselink
Dennis A
DA
Department of Internal Medicine, Renal Transplant Unit, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands. d.a.hesselink@erasmusmc.nl
van Gelder
Teun
T
van Schaik
Ron H N
RH
Balk
Aggie H M M
AH
van der Heiden
Ilse P
IP
van Dam
Thea
T
van der Werf
Marloes
M
Weimar
Willem
W
Mathot
Ron A A
RA
D000328:Adult; D000465:Algorithms; D000483:Alleles; D001499:Bayes Theorem; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005006:Ethnicity; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D016027:Heart Transplantation / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007166:Immunosuppressive Agents; D007527:Isoenzymes; D016572:Cyclosporine; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human