title: Interplay of dissolution, solubility, and nonsink permeation determines the oral absorption of the Hedgehog pathway inhibitor GDC-0449 in dogs: an investigation using preclinical studies and physiologically based pharmacokinetic modeling.
abstract: Factors determining the pharmacokinetics of 2-chloro-N-(4-chloro-3-(pyridine-2-yl)phenyl)-4-(methylsulfonyl)benzamide (GDC-0449) were investigated using preclinical studies and physiologically based pharmacokinetic (PBPK) modeling. Multiple-dose studies where dogs were given twice-daily oral doses of either 7.5 or 25 mg/kg GDC-0449 showed less than dose-proportional increases in exposure on day 1. At steady state, exposures were comparable between the two dose groups. Oral administration of activated charcoal to dogs receiving oral or intravenous GDC-0449 (25 mg) showed a more rapid decrease in plasma concentrations, suggesting that the concentration gradient driving intestinal membrane permeation was reversible. The biliary clearance of GDC-0449 in dogs was low (0.04 ml/min/kg) and did not account for the majority of the estimated systemic clearance (approximately 19% of systemic clearance). Likewise, in vitro studies using sandwich-cultured human hepatocytes showed negligible biliary excretion. The effect of particle size on oral absorption was shown in a single-dose study where 150 mg of GDC-0449 of two particle sizes was administered. An oral PBPK model was used to investigate mechanisms determining the oral pharmacokinetics of GDC-0449. The overall oral absorption of GDC-0449 appears to depend on the interplay between the dissolution and intestinal membrane permeation processes. A unique feature of GDC-0449 distinguishing it from other Biopharmaceutical Classification System II compounds was that incorporation of the effects of solubility rate-limited absorption and nonsink permeation on the intestinal membrane permeation process was necessary to describe its pharmacokinetic behavior.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California 94080, USA. wong.harvey@gene.com
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Frank-Peter
authors.initials: FP
authors.lastname: Theil
authors.forename: Yong
authors.initials: Y
authors.lastname: Cui
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
authors.forename: Laurent
authors.initials: L
authors.lastname: Vernillet
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.forename: Xiling
authors.initials: X
authors.lastname: Song
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Morinello
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
mesh_terms: D000284:Administration, Oral; D000813:Anilides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D002606:Charcoal / Q000494:pharmacology; D003198:Computer Simulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D010316:Particle Size; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D002606:Charcoal