Pharmacogenetic determinants of cyclophosphamide pharmacokinetics in pediatric cancer patients.

Abstract

Purpose: Cyclophosphamide (CY) is an integral component of many combination chemotherapy regimens to treat pediatric cancer patients. Numerous metabolic and transport pathways are involved in the formation and elimination of 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite phosphoramide mustard. We sought to characterize the pharmacogenomic– pharmacokinetic association in pediatric cancer patients. Methods: Seventy-two children less than 21 years old receiving one of six CY-based combination chemotherapy regimens were included. The primary phenotypic endpoint was 4HCY/CY area under the curve (AUC) ratio, which was estimated using noncompartmental analysis after the first CY dose of a cycle. Numerous (N=323) single nucleotide polymorphisms (SNPs) were selected from literature review. DNA was genotyped using Illumina’s GoldenGate genotyping. An additive model for the effect of minor (derived) alleles was fitted for each SNP, adjusting for age and ancestry via principal component decomposition of 31 ancestry informative markers (AIMs) that also were genotyped. Results: The 4HCY/CY AUC ratio was evaluable in 49 children; the ratio decreased as age increased (R2=0.148, p=0.0064). The most significant p-values for association were found for SNPs in ABCC3 (p< 0.01), ABBC4 (p=0.02) and CYP2B6 (p<0.03). There was some suggestion that the association between outcome and the CYP1A1 variant allele present in *2A and *2B might differ by ancestral background. Conclusions: Considerable interpatient variability exists in CY pharmacokinetics, but this was not associated with genetic polymorphisms in pediatric cancer patients.