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 (∼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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.032680.
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ABBREVIATIONS:
- Hh
- hedgehog
- PTCH1
- Patched
- SMO
- Smoothened
- GDC-0449
- 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide
- PBPK
- physiologically based pharmacokinetic
- K2EDTA
- potassium EDTA
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- SI
- small intestine
- GI
- gastrointestinal
- FASSIF
- fasted state simulated intestinal fluid
- SRLA
- solubility rate-limited absorption
- MPER
- maximum permeation extraction ratio
- BEI
- biliary excretion index
- CLbiliary
- biliary clearance
- AUC
- area under the concentration-time curve
- CL
- plasma clearance
- Vss
- volume of distribution at steady state
- AUC0–168
- area under the plasma concentration-time profile from time 0 to 168 h postdose
- AUC0–24
- area under the plasma concentration-time profile from time 0 to 24 h postdose
- BCS
- Biopharmaceutical Classification System.
- Received February 10, 2010.
- Accepted April 20, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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