177: The Effect of a High-Fat Meal on the Pharmacokinetics of Dordaviprone in Healthy Adult Participants

Statement of Purpose: Dordaviprone (ONC201) is a novel, small molecule imipridone with demonstrated antitumor effects in glioma patients(1). As dordaviprone is administered orally, its bioavailability can be impacted by food via changes in gastric emptying, gastrointestinal pH, blood flow or metabolism. This study evaluated the pharmacokinetics (PK) and safety of dordaviprone when administered following a high-fat meal and fasted.

Description of Methods & Materials: This study was a single-center, open-label, randomized, 2-period crossover study conducted with 30 healthy male and female participants. In each period, participants received single dose 625 mg dordaviprone (proposed therapeutic dose) under fasted or fed (after consumption of standardized high-fat meal [800-1,000 calories, ≥50% calories from fat]) conditions. PK blood samples were collected at predose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 and 144 hours postdose in Period 1 and Period 2. Dordaviprone and metabolite ONC207 plasma concentrations were determined by a validated liquid chromatography-tandem mass spectrometry method. PK profiles and PK parameters of dordaviprone and metabolite ONC207, as well as safety profiles were compared between fed and fasted conditions. To assess the effect of food on dordaviprone bioavailability, point estimates and 90% confidence intervals (CIs) were calculated for PK parameters for the ratio of geometric means between dordaviprone administered fed and dordaviprone administered fasted.

Data & Results: All 30 participants were included in the analysis population. Dordaviprone total exposure (AUC) was similar following administration under fed and fasted conditions; peak exposure (C_max) was lower under fed conditions. Geometric mean ratios and 90% CIs of dordaviprone administered under fed compared to fasted conditions fell within bioequivalence limits of 80.00% to 125.00% for AUC_last, and AUC_inf indicating no effect of food on dordaviprone total exposure. Ratios and 90% CIs were 1.00 (0.95 to 1.06) for both parameters. For C_max following fed administration, the geometric mean ratio and 90% CIs fell below bioequivalence limits to 0.61 (0.55 to 0.67) and T_max was delayed by 1.5 hours, indicating the rate of dordaviprone absorption decreased in the presence of food. ONC207 behaved in the same manner displaying lower C_max with delayed T_max, and no impact on AUC. Twenty-nine participants (96.7%) reported treatment emergent adverse events (TEAEs) during the study; all TEAEs were mild. Twenty-one participants (70%) reported treatment-related AEs. The most common dordaviprone-related TEAEs were dizziness, nausea, and headache; all were mild and transient.

Interpretation, Conclusion or Significance: The presence of food (high-fat meal) decreased dordaviprone rate of absorption but did not affect extent of dordaviprone total exposure (AUC). Dordaviprone was well tolerated when administered as single 625 mg doses with or without food. 1 Arrillaga-Romany I, Kurz S, Tarapore R, et al. LTBK-05. Clinical Efficacy of ONC201 in Recurrent H3 K27M-Mutant Diffuse Midline Glioma Patients. Neuro Oncol. 2021;23(Supplement_6):vi230-vi230. doi:10.1093/neuonc/noab196.925.

Disclosures: Angela Bartkus, Marion Morrison, Mark J Mullin, Tim Tippin and Odin Naderer are employees of and have stock ownership in Chimerix Inc. Maggie Anderson and Thangam Arumugham are paid consultants for Chimerix Inc.