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

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.