LB-022 - MULTIPLE ELIMINATION PATHWAYS ARE RESPONSIBLE FOR THE ELIMINATION OF ETRUMADENANT (ETRUMA) AFTER ORAL ADMINISTRATION OF [14C]-ETRUMA TO HUMANS.

L. Adeojo¹, Y. Zhu², L. Jin³, N. Patel⁴, B. Agoram², L. Zhou²; ¹Arcus Biosciences Inc., , United States, ²Arcus Biosciences, , , ³Arcus Bioscience, , , ⁴Certara Simcyp Division, Certara Inc., , .

Background: • Etruma, a selective adenosine A2a/A2b receptor inhibitor, is an orally bioavailable small molecule being evaluated for cancer treatments.

OBJECTIVES
• To determine the overall pathways of metabolism and excretion of etruma.
• To identify circulating metabolites and assess the pharmacokinetics (PK) of [14C]-etruma.

Methods: • A single oral dose of [14C]-etruma 150 mg containing 0.1 mCi radioactivity was administered to 8 healthy male subjects in an open label study. Blood, urine, and fecal samples were collected for 13 days. For each matrix, samples were pooled for total radioactivity (TRA) analysis and metabolite identification.
• Physiologically based PK (PBPK) model was developed using in vitro and clinical data.

Results: • [14C]-etruma was quickly absorbed with a Tmax of 1.5 hrs and T1/2 of 26.6 hrs.
• Etruma and 8 metabolites accounted for 90.9% of the recovered TRA identified in pooled plasma over AUC0-48hrs. The major compounds were etruma O-glucuronide (M2) [43.2%], etruma (31.4%) and N-dealkylated etruma (M1) [15.4%]. Metabolite M1 is inactive, while metabolite M2 is 8.8-fold less potent than etruma.
• At 168 hrs post dose, 93.9% of mean TRA was recovered in urine (54.5%) and feces (39.4%). Of the 93.9% recovered, 91% was identified as etruma and 14 metabolites. M2 and etruma were the most abundant compounds, each accounting for ~30% of total dose. Etruma renal clearance was a minor elimination route.
• Based on TRA recovery in excreta, fraction absorbed (fa) was high. PBPK model approximated fa as 0.9 and fraction metabolized via CYP3A4 as 0.4, reasonably capturing the observed data (Figure 1).
• Etruma was safe and well tolerated.

Conclusion: • [14C]-etruma was absorbed extensively and eliminated completely after a single 150 mg (0.1 mCi) oral dose.
• Etruma was eliminated predominantly by metabolism. CYP3A4 and multiple UGT enzymes mediated its elimination with CYP3A4 responsible for ~40% of the clearance. The identified multiple clearance pathways suggest a low likelihood of strong drug interaction of etruma with CYPs and other metabolic enzymes.
• Etruma, metabolites M1 (inactive) and M2 (8.8-fold less active) were the major circulating drug-related compounds. Further evaluation of the DDI potential of metabolites M1 and M2 as substrates is not needed due to little to no pharmacological activity.