PII-057 - LIMITED DRUG INTERACTION SUPPORTED BY PBPK MODELLING OF ETRUMADENANT (AB928), A NOVEL DUAL ADENOSINE RECEPTOR ANTAGONIST, UNDER COADMINISTRATION WITH A STRONG CYP3A4 AND P-GP INHIBITOR (ITRACONAZOLE) IN HEALTHY PARTICIPANTS.

L. Zhou¹, L. Jin¹, N. Patel², B. Agoram¹; ¹Arcus Biosciences, Hayward, CA, USA, ²Certara, Princeton, NJ, USA.

Background: • Etrumadenant (AB928). Etrumadenant, a selective adenosine receptor antagonist, is an orally bioavailable small molecule being evaluated in clinical trials across multiple oncology indications. CYP3A4 and UDP-glucuronosyltransferases (UGT) were responsible for the primary elimination of etrumadenant in vitro. Etrumadenant is also a P-glycoprotein (P-gp) substrate in vitro.
• Objective. 1) to evaluate the effect of itraconazole on the PK of etrumadenant; 2) to assess the CYP3A4 contribution to overall metabolism using a physiologically based pharmacokinetic (PBPK) model.

Methods: • Clinical Study Design. This was an open-label, fixed-sequence, 2-period drug-drug interaction study to evaluate the effect of multiple oral doses of 200 mg (QD) itraconazole, a strong inhibitor of CYP3A4 and P-gp, on the single dose PK of 150 mg etrumadenant in twenty healthy adult participants.
• PBPK Modeling. A PBPK model with sensitivity analysis on CYP3A4 contribution was developed by using in vitro and clinical data.

Results: • Multiple doses of itraconazole resulted in an increase of approximately 62%, and 18% in etrumadenant AUCinf, and Cmax, respectively, compared to etrumadenant given alone. The limited increase in etrumadenant’s exposure indicates CYP3A4 is partially responsible for the elimination of etrumadenant. The minimal increase (18%) in etrumadenant Cmax suggests coadministration of a P-gp inhibitor does not cause meaningful exposure alteration of etrumadenant.
• PBPK modelling suggested that the fraction of etrumadenant metabolized through CYP3A4 is approximately 0.4.
• All adverse events reported in the study were mild and resolved without treatment.

Conclusion: • In summary, the effect of a strong CYP3A4 inhibitor on the PK of etrumadenant is limited; P-gp may not influence etrumadenant’s oral absorption.