dordaviprone

Acts as a protease activator of the mitochondrial caseinolytic protease P as well as a dopamine antagonist. Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. Dordaviprone activates the integrated stress response, induces apoptosis, and alters mitochondrial metabolism, leading to restored histone H3 K27 trimethylation.

Therapeutic effects:

Decreased progression of glioma.

Pharmacokinetics ⬆ ⬇

Absorption: Extent of absorption following oral administration unknown.

Distribution: Widely distributed to tissues.

Protein Binding: 95–97%.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme, with lesser involvement by the CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5 isoenzymes. Primarily excreted in urine (70%) as metabolites, with 20% excreted in feces.

Half-Life: 11 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1.4 hr	7 days

Contraind./Precautions ⬆ ⬇

Contraindicated in:

OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Congenital long QT syndrome, QT interval prolongation, history of ventricular arrhythmias, electrolyte abnormalities, or HF;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Children <1 yr or <10 kg (safety and effectiveness not established).

Adv. Reactions/Side Effects ⬆ ⬇

CV: DEEP VEIN THROMBOSIS (DVT), QT interval prolongation

Derm: rash

Endo: hyperglycemia, hypoglycemia

F and E: hypocalcemia, hypokalemia, hyponatremia

GI: ↑liver enzymes, constipation, dysphagia, nausea, vomiting, diarrhea

GU: ↓fertility

Hemat: anemia, lymphopenia, neutropenia

MS: muscle weakness, pain

Neuro: ataxia, cranial nerve disorders, dizziness, dysarthria, fatigue, gait disturbance, headache, hemiparesis, peripheral neuropathy, SEIZURE, tremor

Resp: PULMONARY EMBOLISM (PE)

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS)

Interactions ⬆ ⬇

Drug-drug:

QT interval prolonging medications may ↑ risk of QT interval prolongation; avoid concurrent use. If concurrent use necessary, space out administration.
Strong CYP3A4 inhibitors, including itraconazole, or moderate CYP3A4 inhibitors, including erythromycin, may ↑ levels and risk of toxicity; avoid concurrent use. If concurrent use necessary in adults and children weighing ≥52.5 kg, ↓ dordaviprone dose.
Strong CYP3A4 inducers, including rifampin, or moderate CYP3A4 inducers, including efavirenz, may ↓ levels and effectiveness; avoid concurrent use.

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥1 yr and ≥52.5 kg): 625 mg once weekly. Continue until disease progression or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 375 mg once weekly. Continue until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A4 inhibitor: 500 mg once weekly. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and 42.5–<52.5 kg): 500 mg once weekly. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and 27.5–<42.5 kg): 375 mg once weekly. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and 12.5–<27.5 kg): 250 mg once weekly. Continue until disease progression or unacceptable toxicity.
PO (Children ≥1 yr and 10–<12.5 kg): 125 mg once weekly. Continue until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

Capsules: 125 mg

Assessment ⬆ ⬇

Assess for signs/symptoms of ↑ intracranial pressure (headache, nausea, vomiting, altered mental status, changes in pupillary response).
Assess for hypersensitivity reactions (rash, hives, fever, ↓ BP, wheezing, swelling of the face or throat); if anaphylaxis occurs, implement emergent supportive measures (epinephrine) as indicated and hold dordaviprone until symptoms resolve. Permanently discontinue dordaviprone if serious hypersensitivity reactions occur.
Assess for signs/symptoms of DVT (unilateral extremity swelling, pain or tenderness, warmth, erythema, edema) and PE (dyspnea, tachypnea, chest pain, tachycardia, ↓ oxygen saturation, cough, hemoptysis). Monitor for changes in limb circumference.
Assess for seizure activity, including onset, duration, and type of movements, and monitor level of consciousness. Implement seizure precautions as clinically indicated.
Monitor ECG before starting and periodically during treatment as clinically indicated. If QTc interval >500 msec or ↑ of >60 msec from baseline, hold dordaviprone until QTc interval ≤480 msec or returns to baseline. Resume at the next lower dose level. If torsades de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious or life-threatening arrhythmia occur, permanently discontinue dordaviprone.
Assess for other adverse reactions. If Grade 3 or 4, hold dordaviprone until Grade ≤1 or return to baseline. Resume at the next lower dose level. If recurrent Grade 4, permanently discontinue dordaviprone.

Lab Test Considerations:

Verify pregnancy status in women of reproductive potential before starting treatment.
Monitor electrolytes before starting and periodically during treatment as clinically indicated. May ↓ calcium, sodium, potassium, and glucose.
May ↑ AST, ALT, and alkaline phosphatase.
May ↓ hemoglobin, neutrophils, and lymphocytes.

Implementation ⬆ ⬇

PO: Administer on an empty stomach, ≥1 hr before or ≥3 hr after food intake.
Swallow capsules whole. If unable to swallow capsules whole, open each capsule, mix contents with 15–30 mL of liquid (sports drink, apple juice, lemonade, or water) before administration, and administer PO as a liquid. Once mixed, administer within 2 hr, or discard and mix a new dose.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Advise if a dose is missed within 2 days, take the missed dose as soon as possible. If a dose is missed by >2 days, skip the missed dose and take the next dose at the scheduled time.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications.
Advise patient if vomiting occurs after taking a dose, do not take an additional dose and take the next dose at the regularly scheduled time.
Advise patient of hypersensitivity reactions and if signs/symptoms occur, to seek immediate medical attention.
Advise patient that changes in heart rhythm can occur and to seek immediate medical attention if signs/symptoms occur (fast or irregular heartbeat, dizziness, light-headedness, fainting).
Advise patient to notify health care provider or seek medical attention if signs/symptoms of a blood clot in an extremity (swelling, pain, warmth, or redness in an arm or leg) or in the lungs (sudden shortness of breath, chest pain, a fast heartbeat, coughing up blood) occur. Also, advise to seek medical attention for seizure activity (shaking, loss of consciousness, confusion, unusual movements).
Rep: Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected or if breastfeeding. Advise patients of reproductive potential to use effective contraception during treatment and for 1 mo after the last dose. Advise women not to breastfeed during treatment and for 1 wk after the last dose.

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Pronunciation ⬇

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Indications ⬆ ⬇

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