What is already known about this subject • Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFRβ etc. • Sorafenib is clinically approved for treatment of Renal Cell Carcinoma (RCC) and Hepatocellular Carcinoma (HCC) • Sorafenib's pharmacokinetics (PK) is highly variable between subjects • Sorafenib exposure increases less than dose proportionally (likely due to limited solubility) • Sorafenib undergoes enterohepatic recycling (EHC)

What this study adds • First study to characterize the sorafenib PK using a model based on sorafenib's known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of EHC model used a square wave function to describe the gall bladder emptying. • This study evaluated the effect of baseline body weight, BSA, age, gender, liver function parameters, kidney function parameters, and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3, and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified. • This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib.

Aims: To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumors and to evaluate the possible effects of demographic, clinical, and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3, and UGT1A9*5) covariates on the disposition of sorafenib.

Methods: PK was assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphism in metabolic enzymes for sorafenib. Population PK analysis was performed by using the nonlinear mixed effects modeling (NONMEM). Final model was validated using visual predictive checks and nonparametric bootstrap analysis.

Results: A one-compartment model with four transit-absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline body weight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were: clearance 8.13 L/hr (3.6-22.3 L/hr), volume 213 L (50-1000 L), mean absorption transit-time 1.98 hr (0.5-13 hr), fraction undergoing EHC 50%, and average time to gall-bladder emptying 6.13 hours.

Conclusions: Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.