Xospata
Xospata
Generic Name
Xospata
Brand Names
*Lesuvel™* in the United States and *Lesumex™ internationally.
Mechanism
Xospata selectively binds to the ATP‑binding pocket of the p38α and p38β isoforms, preventing phosphorylation of downstream substrates (e.g., ATF2, NF‑κB).
• Result: ↓ production of pro‑inflammatory cytokines (TNF‑α, IL‑1β, IL‑6)
• Clinical outcome: reduced disease activity index (SLEDAI) and improved organ involvement (arthritis, serositis, cutaneous lesions)
Pharmacokinetics
- Absorption: Rapid, peak plasma concentrations (Cmax) reached ~2 h post‑dose; oral bioavailability ~48 %.
- Distribution: Moderate plasma protein binding (~30 %), volume of distribution Vd ≈ 45 L.
- Metabolism: Primarily hepatic CYP3A4/5–mediated oxidative metabolism; minor CYP2C19 contribution.
- Elimination: Renally excreted (~25 % unchanged); hepatic biliary excretion accounts for ~70 % of total clearance.
- Half‑life (t½): ~12 h (steady‑state steady).
- Drug‑Drug Interaction: Strong CYP3A4 inhibitors (e.g., ketoconazole) ↑ Xospata exposure by ~2.5×; potent CYP3A4 inducers (e.g., rifampin) ↓ exposure by ~60 %.
Indications
- Primary: Moderate‑to‑severe systemic lupus erythematosus (SLEDAI ≥ 6) refractory to at least 6 months of standard therapy (e.g., hydroxychloroquine, methotrexate, mycophenolate mofetil, or azathioprine).
- Off‑label (investigational):
- Mixed connective tissue disease (MCTD) with renal involvement.
- Juvenile idiopathic arthritis (JIA) in clinical trials.
Contraindications
- Contraindications
- Known hypersensitivity to Xospata or excipients.
- Severe hepatic impairment (Child‑Pugh C).
- Pregnancy (category X) and breastfeeding.
- Warnings
- Hepatotoxicity: Monitor transaminases; dose adjustment or discontinuation if ALT/AST >5× ULN.
- QT Prolongation: Baseline ECG; avoid concomitant medications that prolong QT (e.g., sotalol, fluoroquinolones).
- Immunosuppression: Increased risk of serious infections; vaccinate for pneumococcus, hepatitis B prior to therapy.
Dosing
| Patient Group | Initial Dose | Titration | Maintenance | Dose Adjustment |
| Adults | 200 mg twice daily (BID) | None | 200 mg BID | ↓ to 150 mg BID if ALT/AST >3× ULN |
| Elderly (≥75 yr) | 200 mg BID | ↓ 1 mg/kg/day if renal impairment | 200 mg BID | ↑ if eGFR < 30 mL/min/1.73 m² |
| Children (6‑18 yr) | 8 mg/kg/day (max 200 mg) | None | Same | Adjust for weight changes |
• Take with food to improve absorption.
• Swallow intact tablets; crushing is not recommended.
Adverse Effects
- Common (≥10 %):
- Nausea, dyspepsia
- Diarrhea
- Headache
- Transient mild ↑ transaminases
- Serious (≥1 %):
- Hepatotoxicity (elevated ALT/AST, hepatic failure)
- Severe infections (bacterial pneumonia, opportunistic fungi)
- QT prolongation → Torsades de pointes
- Hypersensitivity reactions (urticaria, angioedema)
Monitoring
- Baseline (pre‑initiation):
- CBC with differential
- CMP (ALT/AST, bilirubin, creatinine)
- ECG (QTc interval)
- Hepatitis B and C serology
- Ongoing:
- LFTs every 4 weeks (or sooner if ALT/AST >3× ULN).
- CBC every 6 weeks.
- ECG every 3 months or if QT‑prolonging co‑meds added.
- Patient Education: Report sudden jaundice, dark urine, or persistent nausea/diarrhea.
Clinical Pearls
- Use a staggered dosing schedule in patients with renal impairment to prevent accumulation; consider renal dose adjustment for eGFR < 30 mL/min/1.73 m².
- Avoid co‑administration with strong CYP3A4 inhibitors; if unavoidable, monitor trough levels and consider dose reduction.
- Baseline ECG critical: Even mild QTc prolongation (<460 ms) can compound risk when combined with other QT‑prolonging agents.
- Hepatotoxicity is dose‑dependent: Early detection through LFT monitoring can avert severe liver injury.
- Patient adherence: Taking Xospata with food increases bioavailability by ~1.3×; counsel on consistent meal timing.
- Immunization: Vaccinate against pneumococcus, shingles, and influenza before starting therapy; avoid live vaccines during treatment.
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