PT - JOURNAL ARTICLE AU - Hiroyuki Iida AU - Ryu Fujikawa AU - Ryohei Kozaki AU - Ryuichi Harada AU - Yuya Hosokawa AU - Kenichi Ogawara AU - Tomoya Ohno TI - Pharmacokinetic-Pharmacodynamic-Efficacy Modeling of ONO-7579, a Novel Pan-TRK Inhibitor, in a Murine Xenograft Tumor Model AID - 10.1124/jpet.119.264499 DP - 2020 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.119.264499 4099 - http://jpet.aspetjournals.org/content/early/2020/03/26/jpet.119.264499.short 4100 - http://jpet.aspetjournals.org/content/early/2020/03/26/jpet.119.264499.full AB - An 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 TPM3-NTRK1 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 NTRK 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 PK/PD modeling approach in xenograft mice. This finding suggests a rational dosing regimen in early-stage clinical studies for ONO-7579 , a novel pan-TRK inhibitor.