Disposition of GDC-0879, a B-RAF kinase inhibitor in preclinical species.

1. The pharmacokinetics and disposition of GDC-0879, a small molecule B-RAF kinase inhibitor, was characterized in mouse, rat, dog, and monkey. 2. 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. 3. Plasma protein binding of GDC-0879 in mouse, rat, dog, monkey, and humans ranged from 68.8% to 81.9%. 4. In dog, the major ketone metabolite (G-030748) of GDC-0879 appeared to be formation rate limited. 5. 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. [ABSTRACT FROM AUTHOR]