Aim: The pharmacokinetics and pharmacodynamics of vemurafenib are characterized by a wide interpatient variability. Since multiple polymorphic enzymes and drug transporters are involved in vemurafenib pharmacokinetics, we studied associations of polymorphisms on vemurafenib-associated toxicities. Patients & methods: Prospectively collected samples of 97 melanoma patients treated with vemurafenib alone (n = 62) or in combination with cobimetinib (n = 35) were genotyped for ABCB1 (3435C>T), ABCG2 (421C>A, 34G>A) and CYP3A4 (22, 15389C>T) polymorphisms. Associations between these variants and the incidence of toxicities were studied. Results:CYP3A422 was significantly associated with increased risk for grade ≥3 nausea, grade 1-4 hyperbilirubinemia, and cutaneous squamous cell carcinoma. ABCB1 3435C>T was a predictor for grade ≥3 toxicity. Conclusion: Genetic variants in CYP3A4 and ABCB1 are associated with vemurafenib-associated toxicities.

Additional Metadata
Keywords ABCB1, ABCG2, CYP3A4, melanoma, pharmacogenetics, toxicity, vemurafenib
Persistent URL dx.doi.org/10.2217/pgs-2019-0101, hdl.handle.net/1765/122758
Journal Pharmacogenomics
Citation
Goey, A.K. (Andrew Kl), With, M. (Mirjam de), Agema, B.C. (Bram C.), Hoop, E.O.-D. (Esther Oomen-De), Singh, R.K. (Rajbir K.), van der Veldt, A.A. (Astrid Am), … Bins, S. (2019). Effects of pharmacogenetic variants on vemurafenib-related toxicities in patients with melanoma. Pharmacogenomics, 20(18), 1283–1290. doi:10.2217/pgs-2019-0101