PI-069 - FIRST IN HUMAN POPULATION PHARMACOKINETIC ANALYSIS OF THE EGFR INHIBITOR WSD0922-FU.

S. Safgren¹, J. Reid², S. Buhrow¹, W. Zhong³, M. Mrugala⁴, K. Jaeckle⁵, T. Burns¹, S. Kizilbash¹; ¹Mayo Clinic, Mayo Clinic - Rochester, MN, USA, ²Mayo Clinic, Rochester, MN, USA, ³Wayshine Biopharm, Wayshine Biopharm - Shanghai, Shanghai, China, ⁴Mayo Clinic, Mayo Clinic - Phoenix, AZ, USA, ⁵Mayo Clinic, Mayo Clinic - Jacksonville, FL, USA.

Background: WSD0922-FU is an orally administered reversible inhibitor of the epidermal growth factor receptor (EGFR). In this first in human (FIH) study, WSD0922-FU was administered to patients with either high-grade glioma or non-small cell lung cancer with known EGFR signaling pathway activation. A population pharmacokinetic (popPK) model was developed for the Phase I trial with multiple dosing schedules and plasma concentrations from different days and cycles.

Methods: The administration of 40 to 320 mg WSD0922-FU was 1x or 2x daily during the dose escalation phase (25 patients) with rich sampling on C1D1 and C1D15. During the next phase (13 patients) 80 to 160 mg was administered 2x daily, 5-on-2-off schedule, with a rich sampling on C1D1, C2D1 or both. Plasma drug concentrations were measured using an LC-MS/MS method. A popPK model was developed sequentially using the NLME methods and the Phoenix software (Certara). Recruited patients have confirmed disease and EGFR activating mutations.

Results: A 2 compartment (2C) model with 1st-order elimination from the central compartment, Tlag, and absorption transit compartment best described the clinical PK. Covariates (age, gender, race and initial lab values) were not found to influence the PK parameters. A high correlation between clearance and volume was reduced with addition of the transit compartment to a 2C Tlag model then the model was validated using Visual Predictive Check (VPC). The typical value parameter estimates (%CV) are Ka 1.9 hr-1 (23), V 33.5 L (48), V2 400 L (15), Cl 8.3 L/hr (12), Cl2 69.7 L/hr (19), Tlag 0.045 h (15) mean transit time 0.39 h (0.43), number of transit compartments 0.14 (54). The median (CV%) Tmax and Cmax_D during C1D1 was 1.5 h (82) and 6.5 ng/ml/mg (48), respectively.

Conclusion: WSD0922-FU has a high volume of distribution reflecting tissue distribution and the drug lipophilicity but is also rapidly cleared. High variability in the Tmax and dose-adjusted Cmax supports addition of Tlag and transit compartments to the model to account for variability during absorption. Validation using VPC improved with these model additions. The reason for the absorption variability is presently unknown but food-effect is being explored further.