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Published on: September 7, 2013
Characterization of vemurafenib phototoxicity in a mouse model
Stéphanie Marie Boudon1, Ulla Plappert-Helbig, Alex Odermatt
1* Preclinical Safety, Novartis Institutes of BioMedical Research, 4002 Basel, Switzerland.
Abstract:
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.
Insights
Vemurafenib causes dose-dependent phototoxicity in mice, explaining clinical photosensitivity in melanoma patients. Early rat studies missed this risk due to different UV light exposure, highlighting formulation and testing conditions importance.
Area of Science:
- Pharmacology
- Photobiology
- Drug Development
Background:
- Vemurafenib, a B-Raf kinase inhibitor for melanoma, showed early phototoxic potential but was deemed low risk based on rat studies.
- Clinical trials revealed unexpected photosensitivity in patients, creating a discrepancy with preclinical safety assessments.
Purpose of the Study:
- To investigate the discrepancy between preclinical and clinical phototoxicity findings for vemurafenib.
- To evaluate the impact of formulation, dose, treatment duration, and irradiation timing on vemurafenib-induced phototoxicity in vivo.
Main Methods:
- Utilized an established mouse model (oral UV-Local Lymph Node Assay, UV-LLNA) to assess in vivo photosafety.
- Investigated dose- and time-dependent effects of vemurafenib formulations and irradiation parameters.
- Established a basic pharmacokinetic profile in the same mouse strain.
Main Results:
- Demonstrated dose- and time-dependent phototoxicity of vemurafenib tablets in mice.
- Identified the lowest phototoxic dose as 350 mg/kg for 3 days followed by UVA irradiation (10 J/cm²).
- Pure vemurafenib showed no phototoxicity, suggesting formulation significantly impacts risk; differing UV spectrum in rat studies likely explains negative results.
Conclusions:
- Vemurafenib formulations can induce significant phototoxicity, explaining clinical observations in melanoma patients.
- The choice of UV light spectrum and formulation are critical factors in preclinical phototoxicity assessment.
- Re-evaluation of drug photosafety testing protocols is warranted, considering formulation and irradiation conditions.
