Association of Metabolic Genotype Composite CYP3A5*3 and CYP3A4*1B to Tacrolimus Pharmacokinetics in Stable Black and White Kidney Transplant Recipients

Abstract

Interpatient variability in tacrolimus pharmacokinetics is due in part to variation in metabolism by cytochrome P-450 3A5 and 3A4 and membrane transport by P-glycoprotein. We evaluated the combined role CYP3A5*3 and CYP3A4*1B genotypes have on tacrolimus pharmacokinetics in 65 stable Black and White kidney transplant recipients receiving maintenance immunosuppression of tacrolimus and mycophenolic acid. Tacrolimus apparent clearance, trough (C_12h), C_12h/Dose, AUC_0–12, and AUC_0–12/Dose as well as CYP3A5 *3 (rs776746) variants responsible for loss of protein function and CYP3A4-1B (rs2740574) associated with increased CYP3A4 function were assessed. To investigate the association of tacrolimus pharmacokinetics with the CYP3A5 *3 and CYP3A4*1B genotypes, we created a metabolic composite to classify patients as Extensive, Intermediate, and Poor Metabolizers on the basis of the relative expression of specific combinations of CYP3A5 *3 and CYP3A4*1B genotypes. The incorporation of CYP3A5*3 and CYP3A4*1B genotypes that investigate the role of these composite genotypic variants on tacrolimus pharmacokinetics provides additional insights into targeted tacrolimus dosing regimens in these sub-populations. The Extensive Metabolic Composite had twice the dose and toughs when compared to the Poor composite. Approximately 88% of Blacks were classified as Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. The remaining Blacks exhibited loss of function SNPs associated with lower tacrolimus doses comparable to Whites. This is the first report describing the association of CYP3A5*3 and CYP3A4-1B Metabolic Composites on tacrolimus pharmacokinetics in Black and White kidney transplant recipients and provides insight into the interpatient pharmacokinetic variability of this key immunosuppressive drug.