Overview
11 DESCRIPTION Dordaviprone is a protease activator. Dordaviprone is present as dordaviprone hydrochloride with the molecular formula C 24 H 26 N 4 O•2HCl. The molecular weight is 459.41. The full chemical name for dordaviprone hydrochloride is 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2- a ]pyrido[3,4-e]pyrimidin-5(4 H )-one dihydrochloride.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics Cardiac Electrophysiology At 1.2 times the maximum recommended dose, the estimated mean QTcF change was 11.8 msec (90% CI: 9.8, 13.
Indications
- 1 INDICATIONS AND USAGE MODEYSO is indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Common Doses
- 625 mg
- 125 mg
- 250 mg
- 375 mg
Dosage
2 DOSAGE AND ADMINISTRATION • Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens. ( 2.1 ) • Monitor ECG and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated. ( 2.2 ) • The recommended dose in adult patients is 625 mg orally once weekly. ( 2.3 ) • The recommended dose in pediatric patients weighing ≥10 kg is based on body weight (see Table 1). ( 2.3 ) • Take MODEYSO orally once weekly on an empty stomach, at least 1 hour before or 3 hours after food intake. ( 2.
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The following potential clinically significant adverse reactions are described elsewhere in the labelling: • Hypersensitivity [see Warnings and Precautions ( 5.1 )] . • QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] . The most common (≥20%) adverse reactions are fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities are decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. ( 6.
Interactions
- 7 DRUG INTERACTIONS • CYP3A4 Inhibitors: Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO as recommended. ( 2.5 , 7.1 ) • CYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO. ( 7.1 ) • Drugs Known to Prolong QTc Interval: Avoid concomitant use of MODEYSO with products known to prolong the QTc interval. If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product.