title: Clinical Pharmacokinetics of Vemurafenib.
abstract: Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAFV600mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15-21 days and exposure at steady state is relatively constant. Population pharmacokinetic analysis identified a vemurafenib half-life of ≈57 h and elimination appears to be predominantly via the hepatic route. Pharmacokinetic parameters are generally consistent regardless of age, sex or race. No dose adjustments are necessary for patients with mild or moderate hepatic or renal impairment, but the effects of severe hepatic or renal impairment on vemurafenib pharmacokinetics are uncertain. Vemurafenib appears to be a substrate and inducer of cytochrome P450 (CYP) 3A4, a moderate inhibitor of CYP1A2 and both a substrate and inhibitor of the drug efflux transporters P-glycoprotein and breast cancer resistance protein. The relationship between plasma vemurafenib concentrations and response remains to be clarified.
authors.affiliation: Roche Innovation Center New York, 430 East 29th Street, New York, NY, 10016, USA.
authors.forename: Weijiang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Heinzmann
authors.affiliation: Roche Innovation Center New York, 430 East 29th Street, New York, NY, 10016, USA. joseph.grippo@roche.com.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065701:Cytochrome P-450 CYP3A Inducers / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008545:Melanoma / Q000097:blood / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065701:Cytochrome P-450 CYP3A Inducers; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib
keywords: Biopharmaceutics Classification System; Breast Cancer Resistance Protein; Metastatic Melanoma; Tizanidine; Vemurafenib