A phase II clinical trial of sorafenib in androgen-independent prostate cancer: Characterization of pharmacokinetics

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INTRODUCTION: Sorafenib is a novel multikinase inhibitor with activity against Raf/MEK/ERK pathway and tyrosine kinases (VEGFR, PDGFR, c-kit and c-Ret). This open label phase II trial was conducted to determine if sorafenib is associated with a 50%, 4 month probability of progression free survival. The results from pharmacokinetic (PK) characterization for the first stage of this study are described here.
 METHODS: Patients with progressive metastatic androgen independent prostate cancer (AIPC) were enrolled in this study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. The primary endpoint was time to disease progression. Secondary endpoints included measurement of overall response rate and characterization of sorafenib’s PK in patients with AIPC. The blood samples for PK were collected on day 1 and 2 of first cycle; at baseline, 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 hrs after the ingestion of initial doses. Samples were analyzed using a validated LC-MS-MS method. PK parameters were calculated by noncompartmental analysis using WinNonlin professional V 5.0.
 RESULTS: Twenty-two patients (median age 64 years, media PSA at study entry 53.3 ng/mL) were enrolled between Sep 2004 and Apr 2005 for the first stage of this trial. No complete or partial response was observed. Sorafenib was generally well tolerated and had manageable side effects. PK analysis showed the geometric mean for exposure (AUC_0-12) was 9.76 hr*mg/L (95% confidence interval, 6.76-14.09) and for maximum plasma concentration (C_max) was 1.28 mg/L (95% confidence interval, 0.88-1.87). The time to maximum plasma concentration (t_max) ranged from 2 to 12 hr (median 6.01 hrs). The accumulation ratio after second dose ranged from 0.68 to 6.43 (median 1.84), indicating accumulation after multiple dosing, as expected based on sorafenib’s half life of 25-48 hrs.
 CONCLUSIONS: The PK parameters calculated after first oral dose namely C_max' t_max and AUC_0-12 were found to have high overall variability. This variability may be secondary to environmental, physiological, biopharmaceutical and genetic or other non-genetic variables. Evaluation of genetic polymorphism as a contributory factor to variability in PK is currently ongoing.