The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics

Abstract

Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life.

Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer—Evidence for a Relevant Model System and Urine-Based Diagnostic Test

“…All three cell lines with activating BRAF mutations demonstrated greatly increased baseline pMEK levels, but only two of the lines showed dramatic declines in pMEK and reduced proliferation in response to treatment. The concentration of vemurafenib that was applied to the canine InvTCC cells was lower than steady state concentrations achieved in the plasma of humans (53), however, this conservative approach was taken to limit off-target effects of the drug (reviewed in (54)). In the less responsive K9TCC-An line, it is likely that other somatic or inherited mutations modify the effect of the BRAF mutation, and further investigation will elucidate the role of these variants.…”

Variability in bioavailability of small molecular tyrosine kinase inhibitors

“…For most of the smTKIs it has been well established whether they suffer from a change in absorption caused by concomitant [147] ", Increased exposure; ;, lowered exposure; M, no effect; ?, unknown effect; (")/(;)/ (M), possible effect; -, no avoidance needed; A, avoidance needed. WO, without food; F, with food.…”

“…The authorities did not issue an advice concerning food intake yet. A conclusive advice needs to be constructed after thorough interpretation of the study results [147].…”

Drug Interactions in Palliative Cancer Care and Oncology

“…Though the absorption of a single dose of vemurafenib has been shown to increase signifi cantly when administered with a high-fat meal, there is no effect on the terminal half-life, and as such it is diffi cult to determine the impact of high-fat meals on continuous dosing (Ribas et al 2014 ). As a result, the package insert does not stipulate whether vemurafenib should be given with food.…”