A new clinical trial published in Drugs in R&D has revealed that severe renal impairment significantly increases the plasma exposure of dordaviprone, a novel small molecule drug candidate for the treatment of glioma. The study, conducted by researchers including Shamia L. Faison and colleagues, demonstrated that despite dordaviprone being primarily eliminated through non-renal metabolic pathways, participants with severe kidney dysfunction exhibited higher concentrations of the drug in their blood compared to healthy matched controls. This finding suggests that the metabolic enzyme activity responsible for breaking down the drug, specifically cytochrome P450 3A4, may be suppressed in individuals with severe renal impairment, leading to a notable accumulation of the compound in the body.

The research was designed to assess the pharmacokinetic profile of dordaviprone, also known as ONC201, in patients with severe renal impairment. Dordaviprone is a brain-penetrant small molecule imipridone that targets mitochondrial caseinolytic protease P and G protein-coupled dopamine receptor D2. In glioma cells, particularly those with H3 K27M mutations, dordaviprone-mediated agonism of the mitochondrial protease and antagonism of DRD2 result in impaired tumor cell metabolism, mitochondrial damage, and apoptosis. The drug has shown antitumor activity in patients with glioma and is currently enrolling in a phase III clinical trial, making the understanding of its safety and dosing in patients with compromised kidney function a critical area of investigation.

The trial was an open-label, parallel-group, single-period, single-dose study conducted at New Zealand Clinical Research in Christchurch. It involved 16 participants in total, divided into two cohorts of eight individuals each. Cohort 1 consisted of participants with severe renal impairment, defined by an estimated glomerular filtration rate of less than 30 mL/min, while Cohort 2 comprised healthy participants with normal renal function who were matched to the first cohort based on age, body mass index, and sex. All participants received a single oral dose of 375 mg of dordaviprone, administered as three 125-mg capsules with water following a 10-hour fast. The study was approved by an independent ethics committee and adhered to international ethical guidelines and Good Clinical Practice standards.

The primary elimination pathway for dordaviprone is metabolism via cytochrome P450 3A4, with in vitro studies indicating that this enzyme is responsible for a significant fraction of the drug’s metabolism. Previous research in healthy participants confirmed the importance of CYP3A4, showing that coadministration with a strong CYP3A4 inhibitor, itraconazole, increased dordaviprone exposure by 4.4-fold for area under the curve and 1.9-fold for maximum concentration. Despite this primary metabolic route, the study aimed to determine if renal impairment would affect drug levels, given that some drugs cleared primarily by CYP3A4 have shown increased plasma concentrations in patients with kidney disease due to potential suppression of enzymatic activity by uremic toxins or inflammatory cytokines.

Pharmacokinetic analysis revealed that dordaviprone exposure was indeed increased in participants with severe renal impairment. The geometric mean ratios of the severe renal impairment cohort compared with the healthy matched cohort were 1.13 for maximum concentration, 1.48 for area under the plasma concentration-time curve from time zero to time of last measurable plasma concentration, and 1.47 for area under the curve from time zero to infinity. These results indicate that while the peak concentration of the drug increased by approximately 13%, the overall exposure, represented by the area under the curve, increased by roughly 50%. The mean apparent clearance of the drug from plasma was also lower in the renal impairment cohort, suggesting a reduced rate of elimination from the bloodstream.

Urine analysis provided further insight into the elimination mechanisms of dordaviprone. The drug was minimally recovered in urine in both cohorts, with the amount excreted being less than 0.2% of the administered dose. This negligible renal excretion of the parent drug confirms that dordaviprone is not primarily cleared by the kidneys. The similar levels of urinary excretion in both groups reinforce the conclusion that the increased plasma exposure in the renal impairment cohort is not due to a direct change in renal filtration but rather points to alterations in metabolic clearance pathways.

Plasma protein binding was evaluated to determine if changes in drug binding to proteins could account for the observed differences in exposure. The study found no significant difference in the percentage of unbound dordaviprone between participants with severe renal impairment and those with normal renal function. The arithmetic means for the fraction unbound were 3.24% in the renal impairment group and 3.20% in the healthy group. Consequently, the increases in unbound dordaviprone maximum concentration and area under the curve in the severe renal impairment cohort mirrored the trends seen in total dordaviprone levels, indicating that protein binding was not a factor driving the higher exposure in patients with kidney dysfunction.

The safety profile of dordaviprone was assessed through the reporting of adverse events, vital signs, electrocardiograms, and clinical laboratory results. Treatment-emergent adverse events were reported in 75% of participants with severe renal impairment and 62.5% of healthy matched participants. All reported adverse events were mild, and the most common treatment-related event was headache, occurring in 25% of participants in each cohort. The incidence of treatment-related adverse events was 50% in the severe renal impairment group compared with 37.5% in the healthy group. The similarity in the nature and severity of adverse events between the two cohorts suggests that the higher exposure of dordaviprone in patients with severe renal impairment did not lead to a significant increase in safety concerns during the single-dose study period.

The researchers noted that the variable effect of renal impairment on drugs eliminated by CYP3A4 has been attributed to multiple potential reasons, including the presence of additional unknown elimination pathways or changes in protein binding. In this study, the suppression of CYP3A4 activity is the most likely explanation for the increased dordaviprone exposure in participants with severe renal impairment. This hypothesis is supported by the observation that chronic kidney disease can lead to high concentrations of uremic toxins and inflammatory cytokines, which may inhibit enzymatic activity. Although three participants in the renal impairment cohort were taking atorvastatin, a weak CYP3A4 inhibitor, their drug levels were comparable to those not taking the medication, suggesting that atorvastatin was not a major factor influencing the results.

Limitations of the study include the small sample size, with only eight participants in each cohort, which may limit the generalizability of the findings. Additionally, while participants were matched for age, weight, and sex, the renal impairment cohort was allowed to continue their prior medications for the management of renal impairment, which could introduce variability. The study also did not control for pharmacogenomic factors that might influence exposure variability. Despite these limitations, the results provide valuable insights into the pharmacokinetics of dordaviprone in patients with severe renal impairment and will inform dosing paradigms and potential dose adjustments for this population.

The findings of this study will be used to guide the development of dosing recommendations for dordaviprone in patients with renal impairment. The study highlights the importance of considering non-renal metabolic pathways when evaluating drug safety in patients with compromised organ function, particularly for drugs that are primarily eliminated by cytochrome P450 enzymes.

The research underscores the complex interplay between renal function and drug metabolism, demonstrating that even drugs with minimal renal clearance can be affected by kidney disease through indirect metabolic mechanisms. This study contributes to the growing body of evidence that renal impairment can alter the pharmacokinetics of various drugs, necessitating careful consideration in clinical practice. The results will be integrated with patient exposure data in safety exposure response analyses to further refine dosing strategies. As the understanding of dordaviprone’s behavior in different patient populations expands, this trial provides a critical foundation for the safe use of this promising antitumor agent in individuals with severe renal impairment.

Subject of Research: Pharmacokinetics of dordaviprone in participants with severe renal impairment

Article Title: Effect of Severe Renal Impairment on Dordaviprone (ONC201) Pharmacokinetics

Article References: Faison, S. L., Batonga, J., Arumugham, T., Bartkus, A., Morrison, M. E., Mullin, M. J., Tippin, T., & Naderer, O. (2025). Effect of Severe Renal Impairment on Dordaviprone (ONC201) Pharmacokinetics. Drugs in R&D, 25(3), 253-261. https://doi.org/10.1007/s40268-025-00520-x

Image Credits: AI Generated

DOI: 10.1007/s40268-025-00520-x

Keywords: dordaviprone, renal impairment, pharmacokinetics, CYP3A4, glioma, drug metabolism, clinical trial, ONC201, Effect, Severe, Renal, Impairment