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

• Published in: The Journal of pharmacology and experimental therapeutics 2020-06, Vol.373 (3), p.361-369
• Main Authors: Iida, Hiroyuki, Fujikawa, Ryu, Kozaki, Ryohei, Harada, Ryuichi, Hosokawa, Yuya, Ogawara, Ken-ichi, Ohno, Tomoya
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.119.264499

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. 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.