Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms

OBJECTIVETo evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age. METHODSA total of 104 pediatric patients (aged 0.36–16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation. RESULTSIn the whole population, the mean±SD cyclosporine oral bioavailability was 0.38±0.09, volume of distribution was 2.3±0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88±0.16 l/h/kg. The prehepatic extraction ratio was 0.51±0.13, and the hepatic extraction ratio was 0.24±0.04, the former explaining 95% of the variability in oral bioavailability (PT variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P