Effect of Hepatic Impairment on Cobimetinib Pharmacokinetics: The Complex Interplay Between Physiological Changes and Drug Characteristics.

Clinical Pharmacology in Drug Development
Sravanthi CheetiLuna Musib

Abstract

Cobimetinib is a kinase inhibitor indicated for use in combination with vemurafenib for treatment of unresectable/metastatic melanoma with specific BRAF mutations. Cobimetinib is extensively metabolized in liver; thus, patients with hepatic impairment (HI) might have increased cobimetinib exposure. In this study, we investigated the impact of HI on the pharmacokinetics (PK) and safety of cobimetinib. Subjects with normal hepatic function and mild to severe HI were enrolled. All subjects received a single oral dose of 10 mg cobimetinib, and serial blood samples were collected at specified times. Cobimetinib PK in subjects with mild and moderate HI was similar to that in those with normal liver function. However, subjects with severe HI, on average, showed ∼30% lower total AUC0-∞ and ∼2-fold higher unbound AUC0-∞ compared with those with normal hepatic function. These exposure differences can be explained by lower albumin levels observed in subjects with severe HI, the strong correlation between albumin level and the unbound fraction and the general PK variability of cobimetinib. In addition, previous studies with cobimetinib showed a lack of an exposure-response relationship for efficacy and safety. Therefore, collectively, our ...Continue Reading

References

May 1, 1982·Journal of Clinical Pharmacology·D J GreenblattJ Koch-Weser
Mar 1, 1995·Toxicologic Pathology·L Z Benet, P Zia-Amirhosseini
Mar 22, 2002·Clinical Pharmacology and Therapeutics·Leslie Z Benet, Betty-ann Hoener
Dec 2, 2004·Nature Reviews. Cancer·Judith S Sebolt-Leopold, Roman Herrera
Jun 1, 2005·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Fabiola DelcòStephan Krähenbühl
Jan 9, 2007·Current Opinion in Genetics & Development·Nathalie Dhomen, Richard Marais
Sep 3, 2008·European Journal of Clinical Pharmacology·Roger K Verbeeck
Apr 25, 2012·European Journal of Clinical Pharmacology·Paul StatkevichDavid L Cutler
Sep 30, 2014·The New England Journal of Medicine·James LarkinAntoni Ribas
Dec 3, 2014·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Yuzhong DengBrian Dean
Sep 15, 2015·Cancer Chemotherapy and Pharmacology·Kelong HanNageshwar R Budha
Oct 10, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ryan H TakahashiLuna Musib

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