A single‐dose mass balance and metabolite‐profiling study of vemurafenib in patients with metastatic melanoma

Abstract

Vemurafenib, a selective inhibitor of oncogenic BRAF kinase carrying the V600 mutation, is approved for treatment of advanced BRAF mutation–positive melanoma. This study characterized mass balance, metabolism, rates/routes of elimination, and disposition of 14C-labeled vemurafenib in patients with metastatic melanoma. Seven patients with metastatic BRAF-mutated melanoma received unlabeled vemurafenib 960 mg twice daily for 14 days. On the morning of day 15, patients received 14C-labeled vemurafenib 960 mg (maximum 2.56 MBq [69.2 μCi]). Thereafter, patients resumed unlabeled vemurafenib (960 mg twice daily). Blood, urine, and feces were collected for metabolism, pharmacokinetic, and dose recovery analysis. Within 18 days after dose, ∼95% of 14C-vemurafenib–related material was recovered from feces (94.1%) and urine (<1%). The parent compound was the predominant component (95%) in plasma. The mean plasma elimination half-life of 14C-vemurafenib–related material was 71.1 h. Each metabolite accounted for <0.5% and ≤6% of the total administered dose in urine and feces, respectively (0–96 h postdose). No new metabolites were detected. Vemurafenib was well-tolerated. Excretion of vemurafenib via bile into feces is considered the predominant elimination route from plasma with minor renal elimination (<1%).

Effect of Rifampicin on the Pharmacokinetics of a Single Dose of Vemurafenib in Patients With BRAFV600 Mutation–Positive Metastatic Malignancy

“…Limited amounts of metabolites (≤5%) were found in plasma within 48 hours after an oral dose of 14 C‐vemurafenib, with the parent compound vemurafenib being the predominant component (>95%). Over the zero‐ to 96‐hour period, each potential metabolite accounted for <0.5% of the total administered dose in urine and ≤6% of the total administered dose in feces . The limited amounts of metabolites in plasma, urine, and feces suggest that metabolism may not play a critical role in vemurafenib elimination.…”

“…Currently available information suggests that metabolic elimination is unlikely to be the major elimination pathway for vemurafenib. Vemurafenib is predominantly eliminated unchanged via the hepatic route . Preclinical and clinical studies suggest that vemurafenib is 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 (P‐gp) and breast cancer resistance protein …”

“…Vemurafenib is predominantly eliminated unchanged via the hepatic route. 9 Preclinical and clinical studies suggest that vemurafenib is 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 (P-gp) and breast cancer resistance protein. 8,10 CYP3A4 is the most abundant CYP enzyme expressed in the liver and small intestine.…”

“…11 Compounds that activate human pregnane X receptor can induce CYP3A4 and drug metabolism activity, which can affect drug levels and thereby the safety and efficacy of the drug. 10,[12][13][14][15] CYP3A4 has been identified as the oxidative enzyme responsible for vemurafenib metabolism in vitro, [8][9][10] and it is therefore important to assess the effect of CYP3A4 induction on the pharmacokinetics (PK) of vemurafenib in patients.…”

Safe handling of oral antineoplastic medications: Focus on targeted therapeutics in the home setting

“…156 In the first 48 hours, the parent molecule was 38% of the total input dose and metabolites were 2.3%, respectively. From 48 to 96 hours, the parent molecule was 17% of the total input radioactive dose and metabolites were 11.2%, respectively.…”