Journal
PHARMACOGENOMICS
Volume 20, Issue 18, Pages 1283-1290Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/pgs-2019-0101
Keywords
ABCB1; ABCG2; CYP3A4; melanoma; pharmacogenetics; toxicity; vemurafenib
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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:CYP3A4*22 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.
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