Generic Name

Xelstrym

Mechanism

Xelstrym is a novel orally active antiepileptic that:
• Acts as a high‑affinity GABA_B receptor agonist, potentiating inhibitory neurotransmission.
• Exhibits partial antagonism at the NMDA receptor (NMDAR), thereby dampening excitotoxic glutamate currents.
• Inhibits the JAK2/STAT3 signaling pathway in cortical astrocytes, reducing neuroinflammation and seizure‑triggering cytokine release.
• The combined effect leads to decreased neuronal excitability and improved seizure threshold.

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Pharmacokinetics

• Absorption: Rapid, with peak plasma concentrations at ~1 h post‑dose; oral bioavailability ≈ 65 % after first‑pass CYP3A4 metabolism.
• Distribution: Highly protein‑bound (≈ 92 %); crosses the blood‑brain barrier efficiently.
• Metabolism: Hepatic, primarily via CYP3A4; minor contribution from CYP2D6.
• Elimination: 80 % excreted hepatically as metabolites, 20 % renally unchanged.
• Half‑life: ~12 h (steady‑state with twice‑daily dosing).
• Drug interactions: Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) reduce efficacy; strong inducers (rifampin, carbamazepine) accelerate clearance.

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Indications

• Drug‑resistant focal epilepsy (adult and pediatric, 12–18 yrs).
• Adjunctive therapy in status epilepticus refractory to first‑line agents.
• Neuro‑protection in peri‑ictal cerebral ischemia (emerging evidence).

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Contraindications

• Severe hepatic impairment (Child‑Pugh class C); careful dose adjustment otherwise.
• Concomitant use of potent CYP3A4 inhibitors or inducers unless monitored titration.
• Pregnancy: Category B—use only if benefits outweigh risks.
• Serotonergic agents: Risk of serotonin syndrome; avoid co‑prescription with SSRIs/SNRIs or MAOIs without desensitization.
• Monitor for elevated liver enzymes; discontinue if ALT/AST > 3× ULN.

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Dosing

• Do not abruptly discontinue; taper over at least 4 weeks to avoid rebound seizures.
• Counsel patients to take with food to optimize absorption and reduce GI upset.

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Adverse Effects

Common (≥ 10 %)
• Sedation, somnolence, dizziness
• Nausea, dry mouth
• Headache, fatigue

Serious (≤ 2 %)
• Hepatotoxicity (↑ ALT/AST, jaundice)
• Hyponatremia (especially in older adults)
• Serotonin syndrome with concurrent serotonergic therapy
• QTc prolongation (rare, monitor if baseline > 450 ms)

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Monitoring

1. Baseline labs: LFTs, serum sodium, CBC.

2. Follow‑up:
• LFTs and electrolytes at 2 weeks, 2 months, then quarterly.
• ECG at baseline and if QTc > 450 ms.

3. Seizure diary: Log frequency, duration, and precipitating factors.

4. Adverse effect checklist: Report any new symptoms promptly—especially in first 8 weeks.

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Clinical Pearls

• Rapid titration is feasible (¼ dose increase every 2 weeks) in patients needing urgent seizure control, provided close monitoring of plasma levels and LFTs.
• SSRIs + Xelstrym: Initiate SSRI before Xelstrym or add a wash‑out period to mitigate serotonin syndrome.
• Hepatic dosing: In Child‑Pugh B, start at 12.5 mg BID and double only if tolerance is confirmed; never exceed 100 mg/day.
• Avoid alcohol during titration; can amplify sedation and hepatotoxicity risk.
• Overdose: Present with severe somnolence, respiratory depression; supportive care and activated charcoal if < 1 h from ingestion.

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• Xelstrym offers a multi‑mechanistic approach to refractory epilepsy, blending GABAergic potentiation with NMDAR modulation and anti‑inflammatory pathways—key for clinicians aiming for high‑yield therapeutic strategies.