Abstract
The objective of this study was to assess the physiologically based pharmacokinetic (PBPK) model for predicting plasma concentration-time profiles of orally available cMet kinase inhibitors, (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (PF02341066) and 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol (PF04217903), in humans. The prediction accuracy of pharmacokinetics (PK) by PBPK modeling was compared with that of a traditional one-compartment PK model based on allometric scaling. The predicted clearance values from allometric scaling with the correction for the interspecies differences in protein binding were used as a representative comparison, which showed more accurate PK prediction in humans than the other methods. Overall PBPK modeling provided better prediction of the area under the plasma concentration-time curves for both PF02341066 (1.2-fold error) and PF04217903 (1.3-fold error) compared with the one-compartment PK model (1.8- and 1.9-fold errors, respectively). Of more importance, the simulated plasma concentration-time profiles of PF02341066 and PF04217903 by PBPK modeling seemed to be consistent with the observed profiles showing multiexponential declines, resulting in more accurate prediction of the apparent half-lives (t1/2): the observed and predicted t1/2 values were, respectively, 10 and 12 h for PF02341066 and 6.6 and 6.3 h for PF04217903. The predicted t1/2 values by the one-compartment PK model were 17 h for PF02341066 and 1.9 h for PF04217903. Therefore, PBPK modeling has the potential to be more useful and reliable for the PK prediction of PF02341066 and PF04217903 in humans than the traditional one-compartment PK model. In summary, the present study has shown examples to indicate that the PBPK model can be used to predict PK profiles in humans.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035857.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- ADME
- absorption, distribution, metabolism and excretion
- PK
- pharmacokinetics
- CL
- clearance
- Vss
- volume of distribution at steady-state
- Fabs
- fraction absorbed
- Foral
- oral bioavailability
- IVIVE
- in vitro-in vivo extrapolation
- PBPK
- physiologically based pharmacokinetic
- PF02341066
- (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine
- PF04217903
- 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol
- HPLC
- high-performance liquid chromatography
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- AUC
- area under the plasma concentration-time curve
- MLP
- maximum life span
- BRW
- brain weight
- ALS
- allometric scaling
- ACAT
- Advanced Compartmental Absorption and Transit.
- Received August 13, 2010.
- Accepted November 17, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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