Abstract
PF04942847 [2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide] was identified as an orally available, ATP-competitive, small-molecule inhibitor of heat shock protein 90 (HSP90). The objectives of the present study were: 1) to characterize the pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF04942847 to the inhibition of HSP90-dependent protein kinase, AKT, as a biomarker and 2) to characterize the relationship of AKT degradation to tumor growth inhibition as a pharmacological response (antitumor efficacy). Athymic mice implanted with MDA-MB-231 human breast cancer cells were treated with PF04942847 once daily at doses selected to encompass ED50 values. Plasma concentrations of PF04942847 were adequately described by a two-compartment pharmacokinetic model. A time delay (hysteresis) was observed between the plasma concentrations of PF04942847 and AKT degradation; therefore, a link model was used to account for the hysteresis. The model reasonably fit the time courses of AKT degradation with the estimated EC50 of 18 ng/ml. For tumor growth inhibition, the signal transduction model reasonably fit the inhibition of individual tumor growth curves with the estimated EC50 of 7.3 ng/ml. Thus, the EC50 for AKT degradation approximately corresponded to the EC50 to EC80 for tumor growth inhibition, suggesting that 50% AKT degradation was required for significant antitumor efficacy (50–80%). The consistent relationship between AKT degradation and antitumor efficacy was also demonstrated by applying an integrated signal transduction model for linking AKT degradation to tumor growth inhibition. The present results will be helpful in determining the appropriate dosing regimen and guiding dose escalation to achieve efficacious systemic exposure in the clinic.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.181339.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- PKPD
- pharmacokinetic-pharmacodynamic
- HSP90
- heat shock protein 90
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- PF04942847
- 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide
- 17-AAG
- 17-allylamino-17-demethoxygeldanamycin
- 17-DMAG
- 17-dimethylamino-ethylamino-17-demethoxygeldanamycin
- Ce
- effect-site concentration of PF04942847
- Cp
- plasma concentration of PF04942847
- CL
- oral clearance
- E0
- baseline of AKT
- Emax
- maximum effect
- γ
- Hill coefficient
- K1–4
- signal transit compartments
- ka
- absorption rate constant
- KC50
- the plasma concentrations of PF04942847 producing 50% of kmax
- ke0
- the rate constant for equilibration with the effect site
- kmax
- the maximum cell-killing rate constant
- kng
- the first-order tumor net growth rate constant
- obj
- objective function value
- Q
- intercompartmental clearance
- T
- tumor volume
- Tss
- the maximum sustainable tumor volume
- V
- oral volume of distribution
- τ
- mean transit time between the transit compartments.
- Received March 8, 2011.
- Accepted June 15, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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