2606 Background: Single nucleotide polymorphisms (SNPs) in carbonyl reductase 3 (CBR3V244M and CBR3C4Y), may impact the variable pharmacodynamics of anthracyclines. For example, homozygosis for the CBR3 V allele (G) is associated with an 8-fold increased risk for anthracycline-related heart failure. The aim was to develop a population pharmacokinetic model to characterize the metabolism of doxorubicin and explore the influence of CBR3V244M and CBR3C4Y genotype status on the formation of doxorubicinol, a major contributor to doxorubicin-induced cardiotoxocity.METHODSAdvanced breast cancer patients received 60mg/m2 of doxorubicin. Blood was collected over three time windows to capture the PK profile. Doxorubicin and doxorubicinol was measured by UPLC. S-ADAPT-TRAN (v1.56) was used to co-model parent and metabolite data. For simplicity, a single metabolic pathway for doxorubicin was considered. Covariates including age, weight, BSA, and influence of CBR3V244M and CBR3C4Y were explored.RESULTSA total of 34 female patients (79.4% White, 17.6% Black, and 2.9% Native American) were evaluated. Patient demographics including mean (sd) weight, BSA, and age were 81.9kg (20.8), 1.87m2 (0.25), and 51.8 yrs (10.4), respectively. A 4-compartment model best characterized the bi-exponential decay of doxorubicin and doxorubicinol compared to a 3-compartment model (p<0.0033). Model estimated PK parameters were similar to those reported in the literature. The mean (sd) half-life of doxorubicin was estimated as 25.0hr (0.06). CBR3V244M and CBR3C4Y genotype status were similar in Black and White patients (α<0.05). Thus, analysis was conducted without stratifying by geographical ancestry/ethnicity. Patients with homozygous CBR3V244M G genotype status showed greater exposure to doxorubicin (AUC0-inf ) with one (G/A) or two (G/G) copies of the variant allele (p=0.0003).CONCLUSIONSSuccessful model development characterized the pharmacokinetics of doxorubicin and may further elucidate the role of polymorphic CBRs during anthracycline metabolism. Further analyses are ongoing to investigate the influence of age, weight, BSA, CBR3V244M and CBR3C4Y on PK parameters.