PT  - JOURNAL ARTICLE
AU  - Harvey Wong
AU  - Frank-Peter Theil
AU  - Yong Cui
AU  - James C. Marsters, Jr.
AU  - S. Cyrus Khojasteh
AU  - Laurent Vernillet
AU  - Hank La
AU  - Xiling Song
AU  - Hong Wang
AU  - Eric J. Morinello
AU  - Yuzhong Deng
AU  - Cornelis E. C. A. Hop
TI  - 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
AID  - 10.1124/dmd.110.032680
DP  - 2010 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 1029--1038
VI  - 38
IP  - 7
4099  - http://dmd.aspetjournals.org/content/38/7/1029.short
4100  - http://dmd.aspetjournals.org/content/38/7/1029.full
SO  - Drug Metab Dispos2010 Jul 01; 38
AB  - 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 (∼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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics