twice daily. The apparent clearance of vemurafenib in patients with pre-existing mild and moderate renal impairment was similar to that in patients with normal renal function. The potential need for dose adjustment in patients with severe renal impairment cannot be determined as clinical and pharmacokinetic data were available for only one patient [see Use in Specific Populations (8.8)].
Age: Based on the population pharmacokinetic analysis, age has no statistically significant effect on vemurafenib pharmacokinetics.
Body Weight and Gender: Based on the population pharmacokinetic analysis, there was no clinically relevant effect of body weight or gender on vemurafenib pharmacokinetics.
Race: There are insufficient data to eva luate potential differences in the pharmacokinetics of vemurafenib by race.
Pediatrics: No studies have been conducted to investigate the pharmacokinetics of vemurafenib in children.
Drug Interactions: In vitro studies with human hepatic microsomes showed that vemurafenib is an inhibitor of CYP1A2, 2A6, 2C9, 2C19, 2D6, and 3A4/5, with IC50 values of 32.5, > 50, 5.9, 22.5, 33.2, and > 50 µM, respectively.
In an in vivo phenotypic cocktail drug-drug interaction study in patients with cancer, a single dose of the CYP probe substrate cocktail (for CYP1A2, 2D6, 3A4, 2C19 and 2C9) was administered before and concomitantly with vemurafenib (following 15 days of dosing at 960 mg twice daily). Coadministration of vemurafenib increased the AUC of caffeine (CYP1A2 substrate) 2.6-fold and increased the Cmax and AUC of dextromethorphan (CYP2D6 substrate) by 36% and 47%, respectively, while it decreased the Cmax and AUC of midazolam (CYP3A4 substrate) by 35% and 39%, respectively. Coadministration of vemurafenib increased the AUC of S-warfarin (CYP2C9 substrate) by 18%. Coadministration of vemurafenib did not change the systemic exposure to omeprazole (CYP2C19 substrate) [see Drug Interactions (7.1)].
In vitro studies have demonstrated that vemurafenib is both a substrate and an inhibitor of the efflux transporter P-glycoprotein (P-gp).
In vitro studies with human hepatic microsomes showed that vemurafenib is a CYP3A4 substrate. The effect of strong CYP3A4 inhibitors or strong CYP3A4 inducers on the concentrations of vemurafenib has not been eva luated in vivo [see Drug Interactions (7.2)].
12.4 QT Prolongation
The effect of vemurafenib 960 mg administered twice daily on QTc interval was eva luated in a multi-center, open-label, single-arm study in 132 patients with BRAF V600E mutation-positive metastatic melanoma. No large changes in mean QTc interval (i.e., >20 ms) from baseline were detected in the trial. Vemurafenib is associated with concentration-dependent QTc interval prolongation. In the first month of treatment, the largest mean change from baseline of 12.8 ms (upper boundary of the 2-sided 90% confidence interval of 14.9 ms) was observed at 2 hours post-dose on Day 15. In the first 6 months of treatment, the largest observed mean change from baseline of 15.1 ms (upper boundary of the 2-sided 90% confidence interval of 17.7 ms) was detected at a pre-dose time point.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. ZELBORAF increased the development of cutaneous squamous cell carcinomas in patients in clinical trials.
Vemurafenib did not cause gen |
