A single-dose mass balance and metabolite-profiling study of vemurafenib in patients with metastatic melanoma.
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.
Department of Dermatology, University Hospital Zurich Gloriastrasse 31, 8091, Zurich, Switzerland.
Simone M
SM
Goldinger
Department of Dermatology, University Hospital Zurich Gloriastrasse 31, 8091, Zurich, Switzerland.
Jeannine
J
Rinderknecht
Department of Dermatology, University Hospital Zurich Gloriastrasse 31, 8091, Zurich, Switzerland.
Reinhard
R
Dummer
Department of Medical Radiology, University Hospital Zurich Raemistrasse 100, CH-8091, Zurich, Switzerland.
Felix Pierre
FP
Kuhn
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Kuo-Hsiung
KH
Yang
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Lucy
L
Lee
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Ruben C
RC
Ayala
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Jagdish
J
Racha
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Wanping
W
Geng
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
David
D
Moore
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Mei
M
Liu
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Andrew K
AK
Joe
Roche Innovation Center Basel Grenzacherstrasse 124, 4070, Basel, Switzerland.
Selby Patricia Gil
SP
Bazan
Roche Innovation Center New York 430 East 29th Street, New York, New York, 10016.
Joseph F
JF
Grippo
BRAF inhibitor; Vemurafenib; disposition; elimination; mass balance; metabolism; metastatic melanoma