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Research ArticleDrug Discovery and Translational Medicine

Translational Pharmacokinetic-Pharmacodynamic Modeling for an Orally Available Novel Inhibitor of Anaplastic Lymphoma Kinase and c-Ros Oncogene 1

Shinji Yamazaki, Justine L. Lam, Helen Y. Zou, Hui Wang, Tod Smeal and Paolo Vicini
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 67-76; DOI: https://doi.org/10.1124/jpet.114.217141
Shinji Yamazaki
Pharmacokinetics, Dynamics and Metabolism (S.Y., J.L.L., P.V.) and Oncology Research Unit (H.Y.Z., H.W., T.S.), Pfizer Worldwide Research & Development, San Diego, California
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Justine L. Lam
Pharmacokinetics, Dynamics and Metabolism (S.Y., J.L.L., P.V.) and Oncology Research Unit (H.Y.Z., H.W., T.S.), Pfizer Worldwide Research & Development, San Diego, California
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Helen Y. Zou
Pharmacokinetics, Dynamics and Metabolism (S.Y., J.L.L., P.V.) and Oncology Research Unit (H.Y.Z., H.W., T.S.), Pfizer Worldwide Research & Development, San Diego, California
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Hui Wang
Pharmacokinetics, Dynamics and Metabolism (S.Y., J.L.L., P.V.) and Oncology Research Unit (H.Y.Z., H.W., T.S.), Pfizer Worldwide Research & Development, San Diego, California
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Tod Smeal
Pharmacokinetics, Dynamics and Metabolism (S.Y., J.L.L., P.V.) and Oncology Research Unit (H.Y.Z., H.W., T.S.), Pfizer Worldwide Research & Development, San Diego, California
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Paolo Vicini
Pharmacokinetics, Dynamics and Metabolism (S.Y., J.L.L., P.V.) and Oncology Research Unit (H.Y.Z., H.W., T.S.), Pfizer Worldwide Research & Development, San Diego, California
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Abstract

An orally available macrocyclic small molecule, PF06463922 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile], is a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-Ros oncogene 1 (ROS1). The objectives of the present study were to characterize the pharmacokinetic-pharmacodynamic relationships of PF06463922 between its systemic exposures, pharmacodynamic biomarker (target modulation), and pharmacologic response (antitumor efficacy) in athymic mice implanted with H3122 non–small cell lung carcinomas expressing echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutation (EML4-ALKL1196M) and with NIH3T3 cells expressing CD74-ROS1. In these nonclinical tumor models, PF06463922 was orally administered to animals with EML4-ALKL1196M and CD74-ROS1 at twice daily doses of 0.3–20 and 0.01–3 mg/kg per dose, respectively. Plasma concentration-time profiles of PF06463922 were adequately described by a one-compartment pharmacokinetic model. Using the model-simulated plasma concentrations, a pharmacodynamic indirect response model with a modulator sufficiently fit the time courses of target modulation (i.e., ALK phosphorylation) in tumors of EML4-ALKL1196M–driven models with EC50,in vivo of 36 nM free. A drug-disease model based on an indirect response model reasonably fit individual tumor growth curves in both EML4-ALKL1196M– and CD74-ROS1–driven models with the estimated tumor stasis concentrations of 51 and 6.2 nM free, respectively. Thus, the EC60,in vivo (52 nM free) for ALK inhibition roughly corresponded to the tumor stasis concentration in an EML4-ALKL1196M–driven model, suggesting that 60% ALK inhibition would be required for tumor stasis. Accordingly, we proposed that the EC60,in vivo for ALK inhibition corresponding to the tumor stasis could be considered a minimum target efficacious concentration of PF06463922 for cancer patients in a phase I trial.

Footnotes

    • Received May 30, 2014.
    • Accepted July 25, 2014.
  • dx.doi.org/10.1124/jpet.114.217141.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 2014
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Research ArticleDrug Discovery and Translational Medicine

Translational PKPD Modeling of a Novel ALK Inhibitor

Shinji Yamazaki, Justine L. Lam, Helen Y. Zou, Hui Wang, Tod Smeal and Paolo Vicini
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 67-76; DOI: https://doi.org/10.1124/jpet.114.217141

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Research ArticleDrug Discovery and Translational Medicine

Translational PKPD Modeling of a Novel ALK Inhibitor

Shinji Yamazaki, Justine L. Lam, Helen Y. Zou, Hui Wang, Tod Smeal and Paolo Vicini
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 67-76; DOI: https://doi.org/10.1124/jpet.114.217141
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