(W-132) Population Pharmacokinetic Modeling of IMP7068 in Patients with Advanced Solid Tumors

Yiheng Li, NA – Pharmacometrician II, Amador Bioscience, Inc. (Hangzhou); Chih-Yi Hsieh, NA – Executive Vice President & Chief Medical Officer, IMPACT Therapeutics, Inc. (Shanghai); Cong Xu, NA – Chairman, IMPACT Therapeutics, Inc. (Shanghai); Suixiong Cai, NA – Chief Executive Officer, IMPACT Therapeutics, Inc. (Shanghai); Ye Tian, NA – Executive Vice President & & Chief Scientific Officer, IMPACT Therapeutics, Inc. (Shanghai); Huan Xia, NA – Associate Director of Medical, IMPACT Therapeutics, Inc. (Shanghai); Baoyue Li, NA – Executive Director of Biometrics, IMPACT Therapeutics, Inc. (Shanghai); Congcong Zhang, NA – Associate Director of Clinical Biomarker, IMPACT Therapeutics, Inc. (Shanghai); Chongzi Mei, NA – Director of Clinical Operations, IMPACT Therapeutics, Inc. (Shanghai); Jian Wang, NA – Aassociate Director of Clinical Operations, IMPACT Therapeutics, Inc. (Shanghai); Simin Xie, NA – Senior Pharmacometrician, Amador Bioscience, Inc. (Hangzhou); Bing Wang, NA – Chief Executive Officer, Amador Bioscience, Inc. (Pleasanton, CA)

Objectives: IMP7068 is a potent and selective inhibitor of WEE1 kinase. Following oral administration IMP7068 is predominantly metabolized by CYP3A4 in the liver. The major metabolite, IMP7253, is also pharmacologically active. Population pharmacokinetic (PK) modeling was conducted to characterize the concentration-time profiles of IMP7068 and IMP7253 in patients with advanced solid tumors.

Methods: The population PK analysis was based on data from the Phase 1 dose-escalation study (IMP7068-101). The dataset contains 1006 and 1028 quantifiable PK observations of IMP7068 and IMP7253, respectively, from 48 cancer patients at 10 dose cohorts who received orally administered IMP7068. The pooled IMP7068 and IMP7253 PK data were simultaneously modeled using NONMEM (Version 7.4.3). The predictive performances of the final PK model were assessed by goodness-of-fit diagnostics.

Results: A parent-metabolite model was developed to describe the time-dependent PK of IMP7068 and IMP7253 in cancer patients. The PK of IMP7068 was adequately described by a two-compartment model with delayed first-order absorption (mean absorption transit time = 1.42 h) for orally administered IMP7068, and parallel first-order and nonlinear elimination pathways from the central compartment. A one-compartment model was developed for IMP7253, with input assuming the result of IMP7068 metabolism (i.e., the nonlinear elimination pathway of IMP7068). Time-dependent CYP3A4 inhibition was incorporated in the oral bioavailability of IMP7068 and nonlinear clearance of IMP7068 and IMP7253. For the parent drug IMP7068, the estimated apparent clearance of the first-order elimination pathway (CL/F) and steady-state volume of distribution were 125 L/h and 6860 L, respectively. No covariates were added to the combined PK model.

Conclusions: The pooled PK data of IMP7068 and IMP7253 from Study IMP7068-101 was adequately described by a parent-metabolite model with time-dependent oral bioavailability (IMP7068) and nonlinear clearance (IMP7068 and IMP7253). No covariates were added in the final PK model.

Citations: NA