Abstract
The pharmacokinetics and disposition of GDC-0879, a small molecule B-RAF kinase inhibitor, was characterized in mouse, rat, dog, and monkey.
In mouse and monkey, clearance (CL) of GDC-0879 was moderate (18.7–24.3 and 14.5 ± 2.1 ml min−1 kg−1, respectively), low in dog (5.84 ± 1.06 ml min−1 kg−1) and high in rat (86.9 ± 14.2 ml min−1 kg−1). The volume of distribution across species ranged from 0.49 to 1.9 l kg−1. Mean terminal half-life values ranged from 0.28 h in rats to 2.97 h in dogs. Absolute oral bioavailability ranged from 18% in dog to 65% in mouse.
Plasma protein binding of GDC-0879 in mouse, rat, dog, monkey, and humans ranged from 68.8% to 81.9%.
In dog, the major ketone metabolite (G-030748) of GDC-0879 appeared to be formation rate-limited.
Based on assessment in dogs, the absorption of GDC-0879 appeared to be sensitive to changes in gut pH, food and salt form (solubililty), with approximately three- to four-fold change in areas under the curve (AUCs) observed.
Keywords::
Acknowledgements
The authors thanks Array BioPharma chemists for the synthesis of GDC-0879. They also thank Alan Hartford, the DMPK bioanalytical group, and In Vivo Studies group at Genentech, Inc. for their contributions to the statistical analysis of the data, bioanalysis of samples, and for conducting the in-life rodent studies, respectively.
Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.