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


Goldinger, Simone M; Rinderknecht, Jeannine; Dummer, Reinhard; Kuhn, Felix Pierre; Yang, Kuo-Hsiung; Lee, Lucy; Ayala, Ruben C; Racha, Jagdish; Geng, Wanping; Moore, David; Liu, Mei; Joe, Andrew K; Bazan, Selby Patricia Gil; Grippo, Joseph F (2015). A single-dose mass balance and metabolite-profiling study of vemurafenib in patients with metastatic melanoma. Pharmacology Research & Perspectives, 3(2):e00113.

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 (14)C-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 (14)C-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 (14)C-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 (14)C-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%). e00113.

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 (14)C-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 (14)C-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 (14)C-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 (14)C-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%). e00113.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Diagnostic and Interventional Radiology
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:March 2015
Deposited On:19 Mar 2015 07:25
Last Modified:08 Dec 2017 12:33
Publisher:Wiley Open Access
ISSN:2052-1707
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/prp2.113
PubMed ID:25729580

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