Population pharmacokinetic modeling for intravenous temsirolimus and sirolimus metabolite in subjects with various solid tumors

2522 Background: Temsirolimus (TEMSR) is an mTOR inhibitor approved for treatment of patients with advanced renal cell carcinoma, and under development for relapsed/refractory mantle cell lymphoma (MCL). In MCL, TEMSR showed a dose-related increase in median progression-free survival [4.8 vs. 3.4 mo] and objective response rate [22% vs 6%] for 175 mg x 3 wks then 75 or 25 mg weekly regimens (175/75-mg and 175/25-mg), respectively. We aim to characterize the population pharmacokinetic exposure, covariate influence, and differences afforded by these regimens. Methods: Nonlinear mixed-effects models of TEMSR and sirolimus (SIR; major active metabolite) blood concentrations were defined in healthy subjects and patients. Modeling for TEMSR employed a 4-compartment model with saturable distribution to red cells and peripheral tissue, and modeling for SIR utilized a linear 2- compartment model with factor for dose. Covariates included demographic factors, clinical labs, and disease condition. Following validatio...