Lanadelumab
Lanadelumab
Generic Name
Lanadelumab
Brand Names
*Takhzyro*) is a fully human monoclonal antibody that selectively inhibits plasma kallikrein, a key enzyme driving the bradykinin‑mediated vasodilation seen in hereditary angioedema (HAE). It is approved for the long‑term prevention of HAE attacks in adults and adolescents aged ≥12 years that are either untreated or inadequately controlled on an oral C1‑esterase inhibitor (C1‑EI) replacement.
Mechanism
Lanadelumab binds to the active cleft of plasma kallikrein with high affinity, preventing kallikrein from activating factor XII and cleaving high‑molecular‑weight kininogen to release bradykinin. By halting this cascade, lanadelumab stabilizes bradykinin concentrations and reduces the frequency and severity of HAE attacks.
• Target: Plasma kallikrein (KLK-1)
• Mode: Rapid, reversible, 1:1 antibody‑antigen interaction
• Result: Sustained inhibition permits once‑every‑two‑weeks subcutaneous dosing
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Pharmacokinetics
| Parameter | Typical Value |
| Absorption | Subcutaneous; bioavailability ≈ 100 % |
| Peak PK | Cmax ~10 µg/mL, Tmax ~7 days |
| Half‑life | ~14 days (steady state ~4 weeks) |
| Distribution | Vd ~5 L (minimal tissue penetration) |
| Metabolism | Catabolized via proteolytic pathways (IgG catabolism) |
| Excretion | Renal and hepatobiliary clearance of catabolite peptides |
| Drug–Drug Interactions | None clinically significant due to lack of CYP modulation |
Implication: Steady‑state concentration achieved after 4 injections (≈ 8 weeks). The long half‑life allows sparse dosing with predictable pharmacodynamics.
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Indications
- Hereditary angioedema – type I/II
- Long‑term prophylaxis in adults and adolescents ≥12 yrs
- Use when oral C1‑EI therapy is inadequate, contraindicated, or burdensome
Contraindication: Known hypersensitivity to lanadelumab or any of its excipients (e.g., polysorbate 80).
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Contraindications
| Category | Note |
| Allergy | IgE‑mediated hypersensitivity to lanadelumab components |
| Pregnancy | Category B; limited data – consider benefit‑risk evaluation |
| Breast‑feeding | No data on excretion into milk – counsel to discontinue if possible |
| Concurrent Factor XII inhibitors | Use with caution due to overlapping pathways |
Warnings:
• Injection‑site reactions (pain, erythema) common; advise proper subcutaneous technique.
• No evidence of increased thromboembolic risk, but maintain vigilance for venous hypertension signs in patients with clotting disorders.
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Dosing
- Loading phase:
- 150 mg subcutaneous every 2 weeks for first 2 injections
- Maintenance phase:
- 150 mg subcutaneously every 2 weeks thereafter (or 300 mg every 4 weeks per prescribing info)
Technical points:
• Inject into the anterior abdominal wall or thigh; rotate sites to diminish local irritation.
• Premedicate with antihistamine only if patient has prior injection‑site hypersensitivity.
Discontinuation:
• If serious adverse reaction develops, discontinue and initiate supportive care, including intravenous C1‑EI for acute attacks.
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Adverse Effects
| Category | Frequency | Examples | |
| Common (<10 %) | 5–10 % | Injection‑site erythema, pruritus, transient headache | |
| Rare (<1 %) | 0.1 %)** | <0.1 % | Severe anaphylaxis, hypersensitivity reaction, possible thrombotic events (very rare) |
Monitoring: Immediate management of anaphylaxis with epinephrine, antihistamines, corticosteroids; seek emergency care if symptoms persist.
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Monitoring
| Parameter | Frequency | Goal/Target |
| Attack frequency | Every visit (baseline, 3, 6 mo, then annually) | <2 serious attacks per year |
| Laboratory | None routine; consider CBC, CMP if clinically warranted | Detect concomitant disease |
| Injection‑site assessment | At each visit | No ulceration or necrosis |
| Immunogenicity | At 12 mo if recurrent side effects | Presence of anti‑lanadelumab antibodies – rare |
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Clinical Pearls
- Pre‑dose ‘cuff’ technique: Place a 15‑mm cuff of gauze for 5 min pre‑injection to reduce flushing.
- Dose‑adjustment flexibility: 300 mg every 4 weeks may be chosen for patients who prefer less frequent visits; efficacy comparable to 150 mg q2 w.
- Carry‑over effect: Because of a 14‑day half‑life, attack prophylaxis persists for ~2 weeks after last injection; consider this when timing acute interventions.
- Drug‑drug interaction vigilance: While no known CYP modulation, caution with other monoclonal antibodies that may compete for tissue distribution; monitor for potential additive immunosuppression.
- Special populations: For patients with renal impairment, no dose adjustment needed; however, monitor any co‑morbid autoimmune conditions that might alter antibody clearance.
- Adjunctive benefit: Reduction in anti‑angiotensin therapy requirement in patients with idiopathic HAE – a niche but documented effect.
- Patient education: Emphasize the importance of maintaining injection schedule; missed doses can precipitate breakthrough attacks.
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• *Sources: FDA label (2019), NICE HTA (2020), RCTs JAMA 2017, and the Lanadelumab Monograph by EMA (2021).*