Effect of Severe Renal Impairment on Dordaviprone (ONC201) Pharmacokinetics.

Background and objective: Dordaviprone (ONC201) is a novel small molecule with antitumor effects in patients with glioma. The major elimination pathway of dordaviprone is metabolism via cytochrome P450 (CYP) 3A4. This study was designed to assess the effect of severe renal impairment (RI) on dordaviprone pharmacokinetics.

Methods: Eight participants with severe RI and eight participants matched for age, body mass index, and sex, with normal renal function, received a single oral 375-mg dose of dordaviprone. Plasma and urine samples were analyzed for dordaviprone using validated liquid chromatography tandem mass spectrometry methods. Plasma and urine pharmacokinetics, plasma protein binding, and safety profiles were evaluated.

Results: Dordaviprone exposure was increased in participants with severe RI. Geometric mean ratios (90% confidence intervals) of the severe RI cohort compared with the healthy matched cohort were 1.13 (0.92-1.39), 1.48 (0.98-2.23), and 1.47 (0.97-2.21), for maximum concentration (C_max), area under the plasma concentration-time curve from time zero to time of last measurable plasma concentration (AUC_last), and AUC from time zero to infinity (AUC_inf), respectively. Renal clearance of dordaviprone was negligible and similar in both cohorts. Plasma protein binding was similar in both cohorts, leading to similar increases in unbound dordaviprone C_max and AUC in severe RI versus healthy participants. All dordaviprone-related adverse events were mild, occurring in 50% of participants with severe RI and 37.5% of healthy matched participants.

Conclusions: Despite its minimal renal clearance, dordaviprone geometric mean AUC was increased by ~50% in severe RI participants, suggesting CYP3A4 activity may have been suppressed in these participants. The results of this study will be used to inform dordaviprone dosing in patients with RI.

Trial registration number: ACTRN12622000405718; Registered on March 9, 2022. Key Points Dordaviprone is a small molecule drug candidate for the treatment of glioma and is eliminated by non-renal mechanisms. In this clinical trial performed in severely renal-impaired participants, dordaviprone plasma concentrations were increased relative to those observed in healthy participants. This result suggests that the metabolic enzyme activity of CYP3A4 was reduced in severely renal-impaired participants.