Relating Tumor Drug Concentrations To Target Effect With Semi Physiologic Pk-Pd Modeling In Drug Development: An Application Using A Novel Dck Inhibitor

Introduction: While plasma concentrations are commonly studied in preclinical and clinical studies, drug concentrations in tumor and effects on molecular targets may be more appropriate for determining drug dosing and predicting response to therapy. The current study assessed tumor and plasma drug levels of DI87, a novel deoxycytidine kinase (dCK) inhibitor, and determined the relationship to dCK activity using a PET biomarker and imaging. Methods: NSG mice with CEM tumors were treated with DI87 (25 or 50 mg/kg) by oral gavage for a single dose. Tumor and plasma concentrations were assessed over 24 hrs (50 mg/kg dose, 5 times points, N=4 separate mice per time point). Plasma and tumor DI87 concentrations were quantified by LC-MS/MS. dCK activity was determined by PET imaging of a biomarker for dCK activity over 27 hrs ([18F]-clofarabine probe was injected 3 hrs prior to imaging) after a single dose of DI87 (50 mg/kg or 25 mg/kg, 5 time points, 4 mice per time point). Nonlinear mixed effects modeling (NONMEM v. 7.2) was used to build a semi-physiologic pharmacokinetic (PK) model to describe tumor and plasma concentrations (tumor volume fixed to observed median tumor size). The PK model was linked to an inhibitory indirect response pharmacodynamic (PD) model of dCK activity in the tumor using a pooled naive approach to describe the relationship between drug levels in the tumor and dCK inhibition. Results: Peak tumor DI87 concentrations were lower (1.15 ± 0.64 μg/mL vs. 13.5 ± 4.5 μg/mL) and occurred later (9 vs. 3 hr) than peak plasma concentrations. Despite limited tumor sampling, the semi-physiologic model described tumor concentrations well (R 2 =0.71). The PK model had a plasma clearance of 0.52 L/hr/kg with a half-life of 3.7 hr. DI87 exposure in the tumor (AUC) was 17% of that observed in plasma. Maximal and near complete dCK inhibition occurred at 9 hr for both the 50 mg/kg and 25 mg/kg doses with recovery of dCK activity beginning at 27 hr post-dose. The predicted tumor concentration at 12 hr of 0.36 μg/mL was sufficient to maintain maximal dCK inhibition. The initiation of recovery of dCK activity corresponded to the decline in tumor DI87 concentrations, but maintained significant inhibition at 27 hr (25% of baseline). The relationship between dCK activity and DI87 tumor concentrations was well characterized by a sigmoid Emax PD model with a large Hill coefficient. This resulted in a dramatic increase of effect over a small range of concentrations. The EC50 was within the range of tumor concentrations observed in the study (0.21 μg/mL). Conclusions: The use of semi-physiologic PK models that include tumor drug concentrations from limited preclinical data can increase knowledge of the PK-PD for novel therapeutics. This approach enhances understanding of time-dependent effects on molecular drugs targets and can improve selection of rational clinical dosing regimens for phase I clinical trials. Citation Format: Mina Nikanjam, Soumya Poddar, 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 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4064. doi:10.1158/1538-7445.AM2017-4064