vorasidenib
Vorasidenib
Generic Name
Vorasidenib
Mechanism
- Selective dual inhibitor of mutant IDH1 and IDH2 enzymes.
- Blocks conversion of isocitrate to 2‑hydroxyglutarate, the oncometabolite that impairs cellular differentiation.
- Reduces intracellular D‑2‑hydroxyglutarate (D‑2‑HG) levels, enabling leukemic blasts to undergo differentiation and apoptosis.
- Does not inhibit wild‑type IDH, minimizing off‑target effects on normal cells.
Pharmacokinetics
| Parameter | Key Points |
| Administration | Oral tablet, 4 mg once daily (may be taken with or without food; food modestly increases Cmax by ~30 %) |
| Absorption | Rapid, Tmax ≈ 2–3 h; bioavailability ≈ 40 % (CYP3A4‑mediated first‑pass) |
| Distribution | High volume (Vd ≈ 5 L/kg), extensive tissue penetration, CSF levels ~10 % of plasma |
| Metabolism | Predominantly via CYP3A4 (also CYP2B6); glucuronidation contributes minimally |
| Elimination | Primarily fecal (≈ 70 %); renal clearance ~15 % unchanged drug |
| Half‑life | ~20–24 h (steady‑state achieved ≥ 2–3 weeks) |
| Drug Interactions | CYP3A4 inhibitors ↑ vorasidenib exposure; CYP3A4 inducers ↓ exposure; avoid strong CYP3A4 inhibitors (e.g., ketoconazole) without dose adjustment |
Indications
- Relapsed or refractory acute myeloid leukemia (AML) with confirmed IDH1 or IDH2 mutation (FDA‑approved).
- Under investigation in phase III for newly diagnosed IDH‑mutated AML when combined with standard induction or maintenance regimens.
- Trial use in solid tumors (e.g., cholangiocarcinoma) harboring IDH1 mutations (clinical studies only).
Contraindications
| Category | Notes |
| Contraindications | Hypersensitivity to vorasidenib or any excipient. |
| Warnings | Differentiation syndrome (fever, dyspnea, weight gain, hypo‑albuminemia); QT‑interval prolongation; hepatic dysfunction; myelosuppression leading to severe cytopenias; pregnancy (Category D – teratogenic in animal studies). |
| Precautions | Cardiovascular disease, active infection, uncontrolled diabetes, concurrent use of strong CYP3A4 inhibitors/inducers. |
Dosing
- Adults & Adolescents ≥12 y: 4 mg PO once daily (take with water; meal optional).
- Renal impairment (CrCl > 30 mL/min): No dose adjustment.
- Impaired hepatic function (Child‑Pugh A/B): same dose; monitor LFTs.
- Patients on CYP3A4 inhibitors: Reduce dose to 2 mg once daily if concomitant use is unavoidable.
- Patients on CYP3A4 inducers: No adjustment needed; monitor therapeutic response.
- Administration during infusion: Not indicated; oral dosing only.
Adverse Effects
- Common (≥ 15 %) | Incidence |
| Nausea, vomiting, anorexia | 18–25 % |
| Fatigue | 15–20 % |
| Myelosuppression (neutropenia, anemia, thrombocytopenia) | 12–18 % |
| Elevated serum transaminases | 10–12 % |
• Serious (≥ 5 %) | Incidence |
| Differentiation syndrome | 8–10 % |
| QT‑interval prolongation | 5–7 % |
| Severe hepatotoxicity (ALT>5× ULN) | 4–6 % |
| Tumor lysis syndrome | < 3 % |
• Other noteworthy
• Neurotoxicity (rare)
• Hyperglycemia (observed in a subset of patients)
Monitoring
- Baseline | CBC, CMP, electrolytes, ECG, D‑2‑HG plasma level.
- Weekly (first 4 weeks) | CBC, CMP, electrolytes, ECG; assess for differentiation syndrome signs.
- Bi‑weekly (weeks 5–12) | CBC, CMP, ECG, tumor imaging, D‑2‑HG.
- Every 3 months | CBC, CMP, ECG, tumor assessment.
- During differentiation syndrome | Admit for close monitoring; check arterial blood gases, chest imaging.
Clinical Pearls
- Differentiation syndrome is a hallmark of IDH inhibition—initiate low‑dose dexamethasone (4 mg PO BID) prophylactically if patients have high leukocyte counts or symptomatic disease.
- Dose adjustment for CYP3A4 interactions is pivotal; avoid strong inducers (e.g., rifampin) which can render therapy ineffective.
- Cardiac monitoring: Baseline QTc 480 ms or if adding other QT‑prolonging agents.
- Avoid concomitant use with high‑dose vitamin A and other agents that may synergistically increase differentiation syndrome risk.
- Patient education on early recognition of differentiation syndrome (fever, dyspnea, pulmonary infiltrates) and prompt reporting to the care team.
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