LB-015 - FOOD AND CO-ADMINISTRATION OF ACID REDUCING AGENTS (ARAS) HAVE NO CLINICALLY SIGNIFICANT EFFECT ON THE PHARMACOKINETICS OF ETRUMADENANT - A POPULATION PHARMACOKINETIC (POPPK) AND PHYSIOLOGICALLY-BASED MODELING EXPLORATION.

J. Johnson¹, L. Adeojo², K. Liao³, B. Wang⁴, N. Patel⁵, B. Agoram³, L. Zhou³; ¹Arcus Biosciences Inc., , , ²Arcus Biosciences Inc., , United States, ³Arcus Biosciences, , , ⁴Amador Bioscience, Amador Bioscience - Pleasanton, USA, ⁵Certara Simcyp Division, Certara Inc., , .

Background: • Etrumadenant (etruma), a selective adenosine A2a/A2b receptor inhibitor, is an orally bioavailable small molecule being evaluated for cancer treatments.
• Etruma is a weak base with a pH-dependent solubility, potentially subject to absorption related drug interactions with ARAs.
• Many patients on chemotherapy are taking ARAs, and food restrictions limit patient adherence. A preliminary food effect study indicated the effect of food on etruma PK was minimal.

Objectives:
• Use popPK modeling to evaluate the effects of ARAs and food on the PK of etruma.

Methods: • Pooled PK data from a total of 567 subjects were included in model development, 450 cancer patients and 117 healthy volunteers. Dosing ranged between 10-200 mg (QD), given in combination with anti-PD1 agents and/or chemotherapy.
• The final PopPK model of etruma was developed in NONMEM version 7.3.0 or higher using stepwise covariate selection (forward α=0.05, backward α=0.001).
• Covariates considered included meal status (fasted, fed, and unknown), proton pump inhibitors (PPI), H2 antagonists (H2A)/other ARAs, weight, age, sex, kidney/hepatic function, tumor size/type, health status, and other treatments.

Results: • Etruma PK was described by a 2-compartment model with delayed absorption, and first order elimination.
• Weight, age, health status, PPIs, H2A/other ARAs and fasted/fed/unknown meal status were retained in the final popPK model.
• Fasted patients with PPI use decreased etruma Cmax by 16.7% (90% confidence interval: 11.9-21.4%) and AUC by 10.2% (5.2-15.1%, shown in figure in red), compared to patients not using PPIs.
• Use of H2A or other ARAs decreased etruma Cmax by 6.8% (1.4-12.5%) with no effect on AUC (in green).
• Fed condition decreased etruma Cmax by 10.6% (5-16.7%) and increased AUC by 8% (5-13%, in dark blue), compared to fasted patients.
• Patients with PPI use and in fed condition had no impact on AUC compared to patients not using PPIs while fasted (in light blue).
• The AUC decrease in patients with PPI use is attenuated with use of food (compare red to light blue).
• Effect of PPI and food estimated by PBPK modeling is consistent with PopPK results (in black).

Conclusion: • ARAs have no clinically significant effect on the plasma exposure (AUC) of etruma suggesting it can be co-administered with ARAs.
• Food effect is limited, supporting etruma may be taken with or without food.