PII-067 - PHARMACOKINETIC AND PHARMACODYNAMIC MODELING ANALYSIS OF JPI-547 IN PATIENTS WITH ADVANCED SOLID TUMOR.

M. Lee^1,2, S. Choi², S. Lee², J. Kim³, H. Cha³, H. Lim^1,2; ¹Asan Medical Center, Seoul, Republic of Korea, ²University of Ulsan, Seoul, Republic of Korea, ³Onconic Therapeutics, Seoul, Republic of Korea.

Background: JPI-547 is an anti-cancer agent under development that acts as a dual inhibitor of poly(ADP-ribose) polymerase and tankyrase. Reduction of poly(ADP-ribose) (PAR) concentration in peripheral blood mononuclear cell (PBMC) is the biomarker reflecting proposed mechanism of action. To identify the optimal dosing regimen of JPI-547, pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation were performed.

Methods: The concentrations of JPI-547 and its metabolite M1 in plasma and PAR in PBMC were measured for 22 patients with advanced solid tumor who received multiple oral doses of 50, 100, 150 or 200 mg JPI-547 in a phase 1 clinical trial (NCT04335604).
Mixed effects PK-PD model was established sequentially using NONMEM® 7.4.3 (ICON plc, Gaithersburg, MD). Monte Carlo simulations of exposure and response were conducted for various dosing regimens with the established PK-PD model.

Results: PAR level decreased rapidly soon after oral administration of JPI-547 and clear exposure-response relationship was observed. One-compartment PK model with absorption delay and mixed first- and zero-order absorption kinetics best described the observed concentration of parent and metabolite. Response-surface PD model well described the simultaneous effects of JPI-547 and M1 on PAR level.
The half maximal inhibitory concentration (IC50) was estimated to be 67.8 nmol/L for JPI-547 and 145.0 nmol/L for M1. For daily dosing of 50 mg for 5 days in a 7-day cycle, simulation study showed that steady-state average concentration of JPI-547 was 1125.0 nmol/L and that of M1 was 647.4 nmol/L, which exceeded respective IC50 values.

Conclusion: The PK-PD modeling of JPI-547 was successful and the potencies of JPI-547 and M1 were estimated. Simulation study suggests that JPI-547 is expected to exert pharmacologic effect at relatively low doses.