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Research ArticleDrug Discovery and Translational Medicine

Pharmacokinetic-Pharmacodynamic-Efficacy Modeling of ONO-7579, a Novel Pan–Tropomyosin Receptor Kinase Inhibitor, in a Murine Xenograft Tumor Model

Hiroyuki Iida, Ryu Fujikawa, Ryohei Kozaki, Ryuichi Harada, Yuya Hosokawa, Ken-ichi Ogawara and Tomoya Ohno
Journal of Pharmacology and Experimental Therapeutics June 2020, 373 (3) 361-369; DOI: https://doi.org/10.1124/jpet.119.264499
Hiroyuki Iida
Clinical Pharmacology (H.I., T.O.), Research Center of Oncology (R.F., R.K.), and Pharmacokinetic Research Laboratories (R.H., Y.H.), Ono Pharmaceutical Company Limited, Osaka, Japan; and Laboratory of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan (H.I., K.O.)
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Ryu Fujikawa
Clinical Pharmacology (H.I., T.O.), Research Center of Oncology (R.F., R.K.), and Pharmacokinetic Research Laboratories (R.H., Y.H.), Ono Pharmaceutical Company Limited, Osaka, Japan; and Laboratory of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan (H.I., K.O.)
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Ryohei Kozaki
Clinical Pharmacology (H.I., T.O.), Research Center of Oncology (R.F., R.K.), and Pharmacokinetic Research Laboratories (R.H., Y.H.), Ono Pharmaceutical Company Limited, Osaka, Japan; and Laboratory of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan (H.I., K.O.)
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Ryuichi Harada
Clinical Pharmacology (H.I., T.O.), Research Center of Oncology (R.F., R.K.), and Pharmacokinetic Research Laboratories (R.H., Y.H.), Ono Pharmaceutical Company Limited, Osaka, Japan; and Laboratory of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan (H.I., K.O.)
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Yuya Hosokawa
Clinical Pharmacology (H.I., T.O.), Research Center of Oncology (R.F., R.K.), and Pharmacokinetic Research Laboratories (R.H., Y.H.), Ono Pharmaceutical Company Limited, Osaka, Japan; and Laboratory of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan (H.I., K.O.)
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Ken-ichi Ogawara
Clinical Pharmacology (H.I., T.O.), Research Center of Oncology (R.F., R.K.), and Pharmacokinetic Research Laboratories (R.H., Y.H.), Ono Pharmaceutical Company Limited, Osaka, Japan; and Laboratory of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan (H.I., K.O.)
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Tomoya Ohno
Clinical Pharmacology (H.I., T.O.), Research Center of Oncology (R.F., R.K.), and Pharmacokinetic Research Laboratories (R.H., Y.H.), Ono Pharmaceutical Company Limited, Osaka, Japan; and Laboratory of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan (H.I., K.O.)
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Abstract

The orally available and novel small molecule ONO-7579 (N-{2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl}-N′-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea) is a highly potent and selective pan–tropomyosin receptor kinase (TRK) inhibitor. The objective of the present study was to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and antitumor efficacy relationships of ONO-7579 in mice xenografted with a human colorectal cancer cell line, KM12 (harboring the tropomyosin 3 (TPM3)-neurotrophic tyrosine receptor kinase 1 fusion gene), via a PK/PD modeling approach. Plasma and tumor concentrations of ONO-7579, tumor levels of phosphorylated TPM3-TRKA (pTRKA), and tumor volumes in the murine model were measured with a single or multiple dose of ONO-7579 (0.06–0.60 mg/kg) administered once daily. The PK/PD/efficacy models were developed in a sequential manner. Changes in plasma concentrations of ONO-7579 were described with an oral one-compartment model. Tumor concentrations of ONO-7579 were higher than plasma concentrations, and changes in ONO-7579 tumor concentrations were described with an additional tumor compartment that had no influence on plasma concentrations. pTRKA in tumors was described with a direct Emax model, and the tumor ONO-7579 concentration causing 50% of the maximum effect was estimated to be 17.6 ng/g. In addition, a pTRKA-driven tumor growth inhibition model indicated that ONO-7579 started to sharply increase the antitumor effect at pTRKA inhibition rates >60% and required >91.5% to reduce tumors. In conclusion, the developed PK/PD/efficacy models revealed a “switch-like” relationship between pTRKA inhibition rate and antitumor effect in a murine KM12 xenograft model, demonstrating that pTRKA in tumors could serve as an effective biomarker for scheduling the dose regimen in early-stage clinical studies.

SIGNIFICANCE STATEMENT In recent years, clinical development of TRK inhibitors in patients with neurotrophic tyrosine receptor kinase fusion–positive solid tumors has been accelerated. This research found that phosphorylated TRKA was a useful biomarker for explaining the antitumor efficacy of TRK inhibitors using a pharmacokinetic/pharmacodynamic modeling approach in xenograft mice. This finding suggests a rational dosing regimen in early-stage clinical studies for ONO-7579 (N-{2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl}-N′-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea), a novel pan-TRK inhibitor.

Footnotes

    • Received December 18, 2019.
    • Accepted March 23, 2020.
  • This work was funded by Ono Pharmaceutical Company Limited.

  • https://doi.org/10.1124/jpet.119.264499.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 373 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 373, Issue 3
1 Jun 2020
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Research ArticleDrug Discovery and Translational Medicine

PK/PD/Efficacy Modeling of a TRK Inhibitor in Mice

Hiroyuki Iida, Ryu Fujikawa, Ryohei Kozaki, Ryuichi Harada, Yuya Hosokawa, Ken-ichi Ogawara and Tomoya Ohno
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 361-369; DOI: https://doi.org/10.1124/jpet.119.264499

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Research ArticleDrug Discovery and Translational Medicine

PK/PD/Efficacy Modeling of a TRK Inhibitor in Mice

Hiroyuki Iida, Ryu Fujikawa, Ryohei Kozaki, Ryuichi Harada, Yuya Hosokawa, Ken-ichi Ogawara and Tomoya Ohno
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 361-369; DOI: https://doi.org/10.1124/jpet.119.264499
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