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 validation, simulations with variability were used to evaluate effects of covariates on exposure. Results: Final datasets comprised 1342 observations from 150 subjects (TEMSR) and 1648 observations from 279 subjects (SIR). In a typical patient (56-year-old male weighing 76.5 kg), disease affected TEMSR clearance (62.4 L/h in MCL, 92.1 L/h in breast cancer vs. 112 L/h for other subjects). Dose, single vs. multiple, and body weight affected SIR apparent clearance. Simulations for the 175/75-mg regimen indicate that significant covariates yield only modest differences on blood exposures. For MCL (175/75-mg regimen), TEMSR Cmax (week 3) was 2574 ng/mL and SIR Ctrough (week 6) was 10.7 ng/mL. AUC for the 75-mg maintenance arm was ∼2.3-fold (TEMSR) and ∼3.5-fold higher (SIR) than respective values of the 25-mg arm. Correlation of average AUC to clinical response was not apparent. Conclusions: No significant differential effects were observed for age, gender, race, or hepatic and renal laboratory measures. Covariates of disease, while significant, have only modest effects on the exposure profile. Higher clinical responses observed with the 175/75-mg regimen as compared with the 175/25-mg regimen may critically derive from differences in exposure. [Table: see text]