Abstract 2532: Vemurafenib prodrugs suitable for oral and IV administration

Abstract

Abstract Background: The oral therapy vemurafenib was approved by the U.S. FDA in 2011 for first-line treatment of metastatic melanomas. Patients whose tumors carry the BRAF(V600E) mutation are treated with vemurafenib at recommended dose of 960mg twice daily. One reason for such a high dose is due to the poor oral bioavailability of vemurafenib. It was reported that the crystalline formulation of vemurafenib provided only modest drug exposures in animals and human (solubility limited absorption). To increase its oral bioavailability, vemurafenib was subsequently formulated as a micro-precipitated bulk powder (MBP). Despite this special formulation, vemurafenib displayed marked accumulation after repeat dosing at 960 mg BID with high inter-patient variability. Methods and Results: To address the limitation of MBP formulation (e.g., high cost to manufacture and high doses to reach desired drug exposure), we developed prodrugs of vemurafenib, CT207 and CT317, with choices for both oral and i.v. administration. The prodrugs are homologues and freely soluble (>1g/mL) in water as their sodium salts. Both drugs are well-absorbed in dogs and monkeys when dosed in 100% saline solution or in capsule. For example, CT317 reached AUC(0-24) = 256 µMh and 429 µMh (calculated in vemurafenib form) when dosed to dogs at 30 and 50 mg/kg QD (equivalent to 1120 and 1890 mg/day adult dosage). The absolute oral bioavailability of CT207 and CT317 in dogs was consistent at ∼80% in dosing range of 10 to 100 mg/kg, which was approximately 4-times higher than vemurafenib (formulated as MBP). Excellent drug exposure was also observed when CT207 was given to monkeys orally at doses of 50 and 100 mg/kg QD (equivalent to 1120 and 2240 mg/day adult dosage), providing AUC(0-24) = 506 µMh and 955 µMh, respectively. Both CT207 and CT317 showed the same potent antitumor activity as vemurafenib in COLO205 xenograft tumor model, demonstrating the equivalency of tumoricidal effects of the prodrugs to vemurafenib. Conclusions: The consistent high oral bioavailability across wide dosing range and great aqueous solubility of CT207 and CT317 render them to have many advantages over vemurafenib: choices for oral or intravenous administration, reduced daily dose and frequency, and minimized inter-patient variability, among others. Therefore, the prodrugs described here have the potential to complement the clinic use of vemurafenib. Citation Format: Ning Xi, Yingjun Zhang, Zhaohe Wang, Taoxi Lin, Qian Wang. Vemurafenib prodrugs suitable for oral and IV administration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2532. doi:10.1158/1538-7445.AM2014-2532