Pharmacogenetic variants associated with differential sirolimus clearance in pediatric patients.

2562 Background: Sirolimus inhibits the mammalian Target of Rapamycin pathway and is widely used in organ transplantation and treatment of malignancy. CYP3A5*3 polymorphisms have been shown to influence sirolimus clearance in solid organ transplant patients, but effects of other drug metabolism enzyme and transporter (DMET) gene polymorphisms have not been investigated thoroughly. We hypothesized that additional variants, alone or in combination, would better predict sirolimus clearance in pediatric and young adult patients with neurofibromatosis type 1 (NF1) associated plexiform neurofibromas and complex vascular malformations (CVM). Methods: Patients treated with single agent sirolimus (N = 74) had pharmacokinetic parameters including clearance measured in two studies of NF1 and CVM. Patients were genotyped for 1,931 known polymorphisms using the DMET Microarray (Affymetrix). Initial statistical analysis included univariate linear regression on SNPs with a minor allele frequency of > 0.05 for each of th...