title: Pharmacokinetic-pharmacodynamic modeling of biomarker response and tumor growth inhibition to an orally available heat shock protein 90 inhibitor in a human tumor xenograft mouse model.
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 ED(50) 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 EC(50) of 18 ng/ml. For tumor growth inhibition, the signal transduction model reasonably fit the inhibition of individual tumor growth curves with the estimated EC(50) of 7.3 ng/ml. Thus, the EC(50) for AKT degradation approximately corresponded to the EC(50) to EC(80) 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.
authors.affiliation: Department of Pharmacokinetics, Pfizer Worldwide Research and Development, San Diego, California 92121, USA. shinji.yamazaki@pfizer.com
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Leslie
authors.initials: L
authors.lastname: Nguyen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Vekich
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Shen
authors.forename: Min-Jean
authors.initials: MJ
authors.lastname: Yin
authors.forename: Pramod P
authors.initials: PP
authors.lastname: Mehta
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Kung
authors.forename: Paolo
authors.initials: P
authors.lastname: Vicini
mesh_terms: D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015415:Biomarkers; D001798:Blood Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015233:Models, Statistical; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays
chemical_list: C559868:2-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; D000970:Antineoplastic Agents; D015415:Biomarkers; D001798:Blood Proteins; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D051058:Oncogene Protein v-akt