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Disposition of GDC-0879, a B-RAF Kinase Inhibitor in Preclinical Species

Disposition of GDC-0879, a B-RAF Kinase Inhibitor in Preclinical Species

E F Choo, J P Driscoll, J Feng, B Liederer, E Plise, N Randolph, Y Shin, S Wong, Y Ran

Xenobiotica. 2009 Sep;39(9):700-9.

PMID: 19552528

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP905281767	GDC-0879		905281-76-7	Price

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