Characterization of vemurafenib phototoxicity in a mouse model

Vemurafenib is a first-in-class, small molecule B-Raf kinase inhibitor for the treatment of patients with unresectable or metastatic melanoma carrying the BRAFV600E mutation, commercially available since 2011. A general phototoxic potential was identified early during development; however, based on results of an animal study in hairless rats, it was concluded that there would exist no relevant risk for humans. Surprisingly, signs of clinical photosensitivity were reported in many patients during clinical development. Therefore, it became a fundamental question to understand this discrepancy. An established mouse model (oral UV-Local Lymph Node Assay, UV-LLNA) for the assessment of in vivo photosafety was used to investigate the impact of formulations, dose levels, duration of treatment, and timing of irradiation. Moreover, a basic pharmacokinetic profile was established within the same mouse strain. We were able to demonstrate dose- and time-dependent phototoxicity of vemurafenib using commercially available tablets (stabilized amorphous material). The lowest phototoxic dose was 350 mg/kg administrated for 3 consecutive days followed by exposure to UV-visible irradiation at a UVA-normalized dose of 10 J/cm². In comparison, pure vemurafenib, which easily forms crystalline variants and is known to have poor bioavailability, was tested at 350 mg/kg, and no signs of phototoxicity could be seen. The most apparent difference between the early study in hairless rats and this study in mice was the spectral range of the irradiation light source (350-400 nm vs 320-700 nm). Because vemurafenib does not absorb sufficiently light above 350 nm, this difference can easily explain the negative earlier study result in hairless rats.