We previously investigated novel therapies for pediatric ependymoma and found 5‐fluorouracil (5‐FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and simulation approach. Results from our preclinical PK‐PD model suggested tumor concentrations exceeded the 1‐hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK‐PD model to children. To select a 5‐FU dosage for our clinical trial in children with ependymoma, we simulated various 5‐FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5‐FU administration. We developed a pediatric population PK model of bolus 5‐FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1‐hour target exposure for antitumor effect.

Selumetinib (AZD6244, ARRY‐142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N‐desmethyl‐selumetinib in patients with cancer. Concentration–time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N‐desmethyl‐selumetinib data were modeled separately. A sequential zero‐ and first‐order absorption with lag time with a two‐compartment model for selumetinib and a two‐compartment model for N‐desmethyl‐selumetinib best described the concentration–time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body‐surface area based dosing should be used in pediatric patients.

58 Background: Multiple treatment options now exist for metastatic CRPC patients (pts). Germ-line SNPs in docetaxel (D) transport, metabolism, binding site, and degradation genes may contribute to variability in outcomes observed in D treated CRPC pts. Methods: Between 1/07 and 10/08, all PCa pts seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the Prostate Cancer Genetic Risk Evaluation of SNPs Study (PROGRESS). Participants completed a demographic and clinical questionnaire and provided a blood sample. Only CRPC pts treated with D were included in this analysis. Germ-line DNA was analyzed for SNP genotyping on a 128-SNP chip using a TaqMan OpenArray GT Kit (Applied Biosystems). The chip included genes critical to D signaling, transport, and elimination with minor allele frequencies > 5%. Pts were followed for progression-free (PFS) and overall survival (OS). Univariable analyses were performed to identify significant associations between SNP genotype, clinical parameters, and PFS and OS outcomes. Results: 60 pts with metastatic CRPC initiated on D enrolled. Demographics included: age (median) – 69 yrs, ECOG PS 0– 40%, prostate specific antigen (PSA) (median) – 129.9 ng/ml, PSA doubling time (median) – 1.8 months, visceral mets –25%. No clinical parameters were associated with PFS and OS. Significant SNP associations are summarized below. Conclusions: Differences in germ-line ABCG2, ABCB1, and TUBB4 SNPs may contribute to variation in clinical outcomes in CRPC pts treated with D. [Table: see text] [Table: see text]

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