Berotralstat
Berotralstat
Generic Name
Berotralstat
Mechanism
Berotralstat is a reversible, oral, selective inhibitor of plasmin.
• Blocks the conversion of fibrinogen to fibrin cleavage by plasmin, reducing bradykinin production.
• By limiting bradykinin-mediated vascular permeability, it prevents attacks of hereditary angioedema (HAE).
• Unlike other treatments, it functions independently of complement or kallikrein pathways, offering a targeted approach with minimal systemic anticoagulation effects.
Pharmacokinetics
| Parameter | Typical Value | Notes |
| Absorption | Rapid; peak plasma conc. ~1–3 hours post‑dose | Food modestly reduces Cmax but does not alter AUC. |
| Distribution | Volume of distribution ≈ 5 L/kg | High protein binding (~95 %). |
| Metabolism | Primarily *CYP3A4*-mediated oxidation; minor UGT-mediated glucuronidation | Metabolites inactive. |
| Elimination | Dual renal and fecal excretion (≈ 35 % renal) | Half‑life ~8–12 h; suitable for once‑daily dosing. |
| Drug‑Drug Interactions | Inducers/strong inhibitors of CYP3A4 alter exposure; caution with ketoconazole, rifampin, etc. | Avoid co‑admin with potent CYP3A4 inhibitors without dose adjustment. |
Indications
- Prophylaxis of acute attacks in patients with hereditary angioedema (HAE) types I and II (clinical trials: BRISTLE/FUSION).
- Not approved for acute treatment of ongoing swelling episodes.
Contraindications
- Contraindicated: Severe hepatic impairment (Child‑Pugh C), known hypersensitivity to berotralstat or excipients.
- Warnings:
- Bleeding risks: Minimal systemic anticoagulation, but caution in patients on anticoagulants or with platelet disorders.
- Pregnancy/Lactation: Uncertain safety; use only if benefits outweigh risks.
- Drug‑interaction risk: Significant CYP3A4 inhibitors/inducers may necessitate monitoring or dose adjustment.
Dosing
- Recommended dose: 70 mg orally once daily (standard).
- Administration: May be taken with or without food; no specific timing relative to meals.
- Dose adjustments: Currently no formal adjustments for renal impairment; however, monitor therapeutic response.
- Transition: For patients switching from IV/subcutaneous HAE agents, a bridging period of ≤ 1 week is advised.
Adverse Effects
| Category | Frequency | Examples |
| Common (≥ 5 %) | Palpitations, headache, mild abdominal pain. | |
| Less common (1–5 %) | Nausea, dizziness, flushing, rash, joint pain. | |
| Serious (< 1 %) | Bleeding events (epistaxis, gingival bleeding), hypersensitivity reactions, acute liver injury. | |
| Adverse events requiring monitoring | Elevated liver enzymes, anemia, thrombocytopenia. |
Monitoring
- Baseline: CBC, CMP (liver enzymes), coagulation profile if on concurrent anticoagulants.
- Periodic:
- Liver function tests every 3–6 months.
- Platelet count if signs of thrombocytopenia.
- Clinical efficacy: Occurrence of HAE attacks, use of rescue medication.
- If severe reactions: Discontinue and evaluate for underlying causes.
Clinical Pearls
- Early intervention: Starting berotralstat prophylaxis during the first 2–3 years of life optimizes long‑term quality of life in HAE patients.
- Patient education: Emphasize that berotralstat is *not* an emergency abortive agent; patients must still have access to C1‑esterase inhibitor or icatibant for acute swelling.
- Food interaction: While food reduces peak plasma levels slightly, overall AUC remains unchanged; patients can take the drug at any convenient time to improve adherence.
- Polypharmacy checks: Review each patient’s medication list for strong CYP3A4 modulators; consider therapeutic drug monitoring if co‑administration is unavoidable.
- Bleeding safety profile: Unlike kallikrein inhibitors such as ecallantide, berotralstat has a lower risk of bleeding; this can be a deciding factor in patients with concurrent anticoagulation.
- Pediatric use: Limited data in < 12 yr; currently approved only for adults and adolescents ≥12 yrs.
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• *Berotralstat* serves as a pivotal oral prophylactic for HAE, leveraging plasmin inhibition to reduce bradykinin synthesis while maintaining a favorable safety and pharmacokinetic profile suitable for chronic use.