Abstract 3881: Relating tumor drug concentrations to target effect with semi physiologic PK-PD modeling in drug development: An application using a novel dCK inhibitor

Abstract

Abstract Introduction: Deoxycytidine kinase (dCK) is essential for DNA synthesis through salvage pathways and DI-87 is a novel dCK inhibitor in preclinical development. This study used PET imaging to measure dCK inhibition and pharmacokinetic-pharmacodynamic (PK-PD) modeling to relate tumor drug levels to tissue with dCK activity and tumor shrinkage. Methods: Oral DI-87 was administered to NSG mice with plasma and tumor PK assessed over 24 hrs by mass spectrometry. NSG mice with CEM tumors were administered varying doses of DI-87 followed by the [18F]CFA PET probe and PET imaging. NSG mice with CEM tumors were administered thymidine and DI-87 concurrently and tumor growth monitored. PK-PD modeling was conducted with NONMEM (v. 7.3). Results: DI-87 plasma concentrations peaked at 3 hr; tumor peak concentrations occurred later. Tumor concentrations were less than one third of plasma concentrations. Full dCK inhibition by PET imaging occurred between 10 and 25 mg/kg and decreasing doses led to faster recovery of activity. Full recovery of enzyme activity occurred by 36 hrs with full inhibition being maintained at the 12 hr time point at the 25 mg/kg dose. Maximal growth inhibition occurred with full dCK inhibition over the dosing range (25 mg/kg BID) when DI-87 was given in combination therapy with thymidine; thus increased doses led to more persistent dCK inhibition with predictable increased growth inhibition. Conclusions: Combining PET probes with PK-PD modeling led to an optimized dosing schedule for combination therapy with DI-87. Citation Format: Soumya Poddar, Mina Nikanjam, Edmund Capparelli, Thuc Le, Liu Wei, Caius Radu. Relating tumor drug concentrations to target effect with semi physiologic PK-PD modeling in drug development: An application using a novel dCK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3881.