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.
Choo
E F
EF
Drug Metabolism and Pharmacokinetics Department, Genentech, Inc., South San Francisco, CA 94080, USA. echoo@gene.com
Driscoll
J P
JP
Feng
J
J
Liederer
B
B
Plise
E
E
Randolph
N
N
Shin
Y
Y
Wong
S
S
Ran
Y
Y
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006207:Half-Life; D006801:Humans; D007192:Indenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
C540167:2-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol; D001798:Blood Proteins; D007192:Indenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048493:Proto-Oncogene Proteins B-raf