Dordaviprone

Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P (ClpP). Dordaviprone also inhibits the dopamine D2 receptor.

Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. In-vitro, dordaviprone activated the integrated stress response, induced apoptosis, and altered mitochondrial metabolism leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma models.

Dordaviprone exhibited antitumor activity in cell-based assays and in vivo models of H3 K27M-mutant diffuse glioma.

Cardiac Electrophysiology

At 1.2 times the maximum recommended dose, the estimated mean QTcF change was 11.8 msec (90% CI: 9.8, 13.7).

Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of dordaviprone have not been fully characterized.

Dordaviprone pharmacokinetics were predicted following a single dose in patients at the approved recommended dosage and are presented as mean (CV%) unless otherwise specified. Dordaviprone maximum concentration (C_max) is 2.8 mcg/mL (42%), and total systemic exposure (AUC) is 23 hr·mcg/mL (48%). Dordaviprone C_max and AUC increased in a dose proportional manner over the dose range of 125 to 625 mg. No accumulation is observed following once weekly dosing.

Absorption

Dordaviprone median (min, max) time to maximum plasma concentration (T_max) is 1.4 hours (0.5, 5.6 hours).

Food Effect

Dordaviprone C_max decreased by 40% with no change on AUC following administration with a high-fat meal (800 to 1,000 calories, 50% fat).

Distribution

Dordaviprone apparent (oral) volume of distribution is 450 L (40%).

Dordaviprone plasma protein binding is 95% to 97% and independent of concentrations in vitro.

The median blood-to-plasma ratio is 0.67 in vitro.

Metabolism

Dordaviprone is primarily metabolized by CYP3A4 with minor contribution from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5.

Excretion

Dordaviprone mean terminal half-life is 11 hours (30%), and the apparent clearance is approximately 27 L/hr (48%).

Following a single dose of radiolabeled dordaviprone, 70% of the dose was recovered in urine and 20% in feces with no notable unchanged dordaviprone in urine or feces.

Specific Populations

No clinically significant differences in the pharmacokinetics of dordaviprone were observed based on age (3 to 90 years), sex, race (74% White, 9% Black or African American, or 5% Asian) or mild hepatic impairment (total bilirubin ≤ULN with AST >ULN or total bilirubin >1 to 1.5 times ULN with any AST).

The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on dordaviprone pharmacokinetics is unknown.

Pediatric Patients

The exposure of dordaviprone in pediatrics weighing 10 kg and higher is predicted to be within the range of exposures predicted in adults at the recommended dosage.

Renal Impairment

Following a single oral dose of 375 mg (0.6 times the maximum approved recommended dose), dordaviprone AUC increased by 1.5-fold and C_max by 1.1-fold in subjects with severe renal impairment (CLcr <30 mL/min, estimated by the Cockcroft-Gault equation).

Hepatic Impairment

Following a single oral dose of 125 mg (0.2 times the maximum approved recommended dose) dordaviprone AUC increased by 1.5-fold and C_max by 1.2-fold in subjects with moderate hepatic impairment (Child Pugh class B).

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

CYP3A4 Inhibitors: Dordaviprone C_max increased by 2-fold and AUC increased by 4-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor) 200 mg once daily for 8 days. Dordaviprone C_max is predicted to increase by ~1.5-fold and AUC by 2.5-fold following concomitant administration of fluconazole or erythromycin (moderate CYP3A4 inhibitor).

CYP3A4 Inducers: Dordaviprone C_max is predicted to decrease by 68% and AUC by 83% following concomitant administration of rifampin (strong CYP3A4 inducer) and dordaviprone C_max is predicted to decrease by 44% and AUC by 65% following concomitant administration of efavirenz (moderate CYP3A4 inducer).

Other Drugs: No clinically significant difference in dordaviprone pharmacokinetics is predicted when used concomitantly with cimetidine (weak CYP3A4 inhibitor).

No clinically significant difference in dordaviprone pharmacokinetics is observed with multiple doses of a rabeprazole (proton-pump inhibitor).

No clinically significant differences in the pharmacokinetics of the following drugs are predicted following concomitant use with dordaviprone: dabigatran etixelate (P-gp substrate), rosuvastatin (BCRP substrate), midazolam (CYP3A substrate), desipramine (CYP2D6 substrate) and repaglinide (CYP2C8 substrate).

In Vitro Studies

CYP Enzymes: Dordaviprone inhibits CYP1A2, CYP2B6, and CYP2C19 and induces CYP2B6.

Transporter Systems: Dordaviprone inhibits MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, and OCT1.

The nonclinical safety profile of dordaviprone reflects the on-target pharmacology and dopamine receptor inhibition. In repeat-dose toxicology studies of up 13 weeks in duration, weekly oral administration of dordaviprone to dogs caused central nervous system-related toxicities including whole body tremors, cranial tremors, seizures, excessive salivation, lateral recumbency, rigidity, paddling of limbs, overall rigid body, salivation, abnormal gait/stance, and twitching at doses resulting in less than or equal to 0.7 times the human exposure at the highest recommended dose based on AUC. In a 13-week repeat-dose toxicology study in rats, mammary gland hyperplasia occurred at doses resulting in 0.11 times the human exposure at the highest recommended dose based on AUC.