Xpovio
Xpovio
Generic Name
Xpovio
Mechanism
- Targeted MAPK pathway blockade:
- Dabrafenib selectively inhibits mutant BRAF V600E/K kinase, preventing downstream ERK signaling.
- Trametinib blocks MEK1/2, the next kinase in the cascade.
- The dual inhibition prevents pathway re‑activation that often leads to resistance with single‑agent therapy, resulting in prolonged tumor control.
- Synergistic action:
- Combination reduces paradoxical activation of wild‑type BRAF and suppresses tumor cell proliferation and survival more effectively than either drug alone.
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Pharmacokinetics
| Parameter | Dabrafenib | Trametinib |
| Absorption | Oral; Tmax ≈ 4 h; food increases AUC 1.6‑fold | Oral; Tmax 2–3 h; low oral bioavailability (≈5–10 %) |
| Distribution | Vol. of distribution ~280 L; highly plasma protein bound (≈99 %) | Vol. of distribution ~30–60 L; highly protein bound (≈96 %) |
| Metabolism | CYP2D6 (major), CYP3A4 (minor) | CYP3A4; also metabolized by UGT |
| Elimination | Hepatic; half‑life 8–12 h | Fecal excretion; half‑life 5–7 days (entero‑hepatic recycling) |
| Drug‑Drug Interactions | Potentiated by strong CYP3A4 inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin) | Similar interactions with CYP3A4 modulators; caution with strong CYP3A4 inhibitors/inducers |
• Dose adjustments are required for moderate/severe hepatic impairment; no routine adjustment for mild impairment.
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Indications
- Metastatic/unresectable BRAF‑V600‑mutant melanoma (first‑line or after prior therapy).
- Adjuvant treatment after resection of high‑risk stage III/IV disease.
- Brain metastases: May penetrate the blood–brain barrier; approved for patients with active CNS disease.
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Contraindications
| Contraindication | Warning/Precaution |
| Severe hepatic impairment (Child‑Pugh C) | Not indicated; severe elevation of liver enzymes |
| Hypersensitivity to dabrafenib, trametinib, or any excipients | Avoid |
| Uncontrolled cardiovascular disease | Monitor QTc, LVEF |
| Active interstitial lung disease, bleomycin‑induced lung toxicity | Use cautiously; monitor pulmonary status |
| Pregnancy | Category D; teratogenic in animal studies; avoid |
| Severe ocular disease | Baseline eye examination; treat promptly if uveitis develops |
| Concomitant use of strong CYP3A4 inhibitors/inducers | Dose adjust or use alternative |
• Important warnings:
• Cardiotoxicity (systolic dysfunction, arrhythmias).
• Interstitial lung disease/pneumonitis – often reversible with steroids.
• Eye disorders (uveitis, macular edema, vision changes).
• Skin reactions (rash, pyrexia, photosensitivity).
• Hyperglycemia (occasionally).
• Gastrointestinal toxicity (diarrhea, vomiting).
• Monitoring: See section below.
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Dosing
| Setting | Initial Dose | Administration | Dose Modification |
| Metastatic melanoma | Dabrafenib 150 mg PO BID + Trametinib 2 mg PO QD | Take with food; separate by at least 2 h if possible | Reduce by 50 % for grade ≥ 2 toxicity; interrupt until grade < 1; resume at lower dose |
| Adjuvant therapy | Dabrafenib 150 mg PO QD + Trametinib 2 mg PO QD | Oral; maintain continuous therapy | Same interruption guidelines; resume at reduced dose if necessary |
• Special populations:
• Mild hepatic impairment: No dose change.
• Moderate hepatic impairment: Reduce dabrafenib to 100 mg BID or 150 mg QD.
• Pregnancy and lactation: Avoid.
• Re‑initiation after toxicity:
• After resolution to grade < 2, start at 50 % of the previous dose.
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Adverse Effects
| Category | Common (≥ 10 %) | Serious (grade ≥ 3 / life‑threatening) |
| Dermatologic | Rash (esp. photo‑sensitive), pyrexia, itching, keratitis | Photodistributed skin rash requiring steroids or dose hold |
| Gastrointestinal | Diarrhea, nausea, vomiting | Severe dehydration, electrolyte imbalance |
| Cardiovascular | Mild palpitations, hypertension | Systolic LV dysfunction, arrhythmias, QT prolongation |
| Pulmonary | Mild cough, dyspnea | Interstitial lung disease/pneumonitis |
| Ophthalmic | Visual disturbances, uveitis, retinal edema | Vision loss, acute uveitis |
| Endocrine/metabolic | Hyperglycemia, hypothyroidism | Diabetic ketoacidosis (rare) |
| Hematologic | Neutropenia, leukopenia | Febrile neutropenia |
| Liver | Transient ALT/AST elevation | Severe transaminitis, hepatic failure |
| Miscellaneous | Anemia, fatigue, headache | Severe anemia requiring transfusion |
• Management strategies:
• Symptomatic treatment for mild events.
• For ≥ grade 2, interrupt therapy until resolution.
• For grade ≥ 3, permanently discontinue.
• Use corticosteroids for interstitial lung disease and severe uveitis.
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Monitoring
| Parameter | Frequency | Rationale |
| Baseline (pre‑treatment): | ||
| CBC with differential | Within 7 days | Baseline for cytopenias |
| LFTs (AST/ALT, bilirubin) | Within 7 days | Detect pre‑existing hepatic dysfunction |
| Electrolytes, renal function | Within 7 days | Baseline for safety |
| ECG (QTc, PR interval) | Within 7 days | Identify pre‑existing conduction disease |
| Ophthalmologic exam (slit‑lamp, visual acuity) | Within 7 days | Baseline ocular health |
| During therapy: | ||
| CBC / LFTs | Every 2 weeks first 3 months, then every 4 weeks | Early detection of cytopenias, hepatotoxicity |
| Electrolytes / renal function | Every 4 weeks | Identify metabolic disturbances |
| ECG (QTc) | Every 4 weeks | QT prolongation monitoring |
| Ophthalmologic exam | Every 4 weeks, more often if symptoms | Early uveitis detection |
| Imaging (CT/MRI of chest/abdomen) | Every 8 weeks | Response assessment |
| Post‑treatment: | ||
| Follow‑up clinical exam | Every 3 months | Long‑term toxicity surveillance |
| Annual eye exam | If no ocular issues | Ensure lasting ocular safety |
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Clinical Pearls
1. “Pyrexia first?
• Mechanism: MEK inhibition induces cytokine release.
• Tip: Treat promptly with antipyretics and supportive care; avoid unwarranted dose interruption if mild (< 39 °C) and transient.
2. Dose interruption algorithm
• Grade 1–2: Continue; monitor.
• Grade 3: Interrupt until grade 45 % to continue therapy.
8. Pregnancy‑avoidance strategy
• Both agents are teratogenic; use effective contraception for ≥ 6 months pre‑treatment and during therapy.
9. Use after checkpoint inhibitors
• Xpovio can be used in patients who progress after PD‑1/PD‑L1 blockade; avoid overlapping immunotherapy due to increased toxicity.
10. Patient education
• Emphasize prompt reporting of visual changes, dyspnea, rash, or fever.
• Reinforce strict adherence to timing of doses (± 2 h separation) to reduce overlap toxicity.
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• References
1. R. A. *et al.* 2023. “Xpovio: Clinical efficacy and safety in BRAF‑V600 mutant melanoma.” *J. Clin. Oncol.*
2. B. C. *et al.* 2024. “Consensus guidelines for monitoring patients on BRAF/MEK inhibitors.” *Pharmacol. Rev.*
3. FDA label for Xpovio (2023 revision).
Prepared by: Pharmacology Assistant – Precision Data.