Generic Name

Tysabri (natalizumab)

Mechanism

• α4‑integrin blockade: Natalizumab binds the α4 subunit (α4/β1 integrin and α4/β7 integrin) on leukocytes.
• Inhibition of leukocyte adhesion and migration: Prevents leukocytes from tethering to vascular cell adhesion molecule‑1 (VCAM‑1) on endothelium, thereby reducing neuroinflammation and gastrointestinal transmigration.
• Resulting reduction of CNS inflammatory lesions and intestinal flare‑ups.

Pharmacokinetics

• Route: Intravenous infusion (loading dose 300 mg, maintenance 300 mg IV every 4 weeks).
• Bioavailability: 100 % (IV).
• Half‑life: ~11 days (steady‑state reached after 4–6 months).
• Volume of distribution: Low, reflecting limited tissue penetration beyond the vascular compartment.
• Clearance: Linear, predominantly via reticuloendothelial system; no renal or hepatic dose adjustments required.
• Immunogenicity: Low incidence of anti‑natalizumab antibodies; no clinically relevant impact on efficacy.

Indications

• Relapsing‑remitting multiple sclerosis – first‑line or second‑line therapy for patients with inadequate response to interferon‑β/GLAT or other disease‑modifying treatments.
• Moderately severe Crohn’s disease – for patients refractory to or intolerant of conventional immunosuppressants (azathioprine, methotrexate, anti‑TNFα).

Contraindications

• Known hypersensitivity to natalizumab or any excipients.
• Active uncontrolled infections (especially HIV, HBV).
• Evidence of Progressive Multifocal Leukoencephalopathy (PML) – history of fingolimod exposure or ongoing PML risk factors.
• Pregnancy – Category X; teratogenic potential.
• Concurrent use of rituximab – increased PML risk.
• JC virus (JCV) seropositivity – risk of PML increases; baseline & periodic monitoring required.

> Warning: PML is the most serious adverse event; risk is heightened in JCV‑positive patients, especially after ≥ 24 months of therapy or with prior immunomodulators. Early detection and immediate drug discontinuation are critical.

Dosing

• No dose adjustment for renal or hepatic impairment.
• Reconstitution: Dilute in 500 mL of 0.9 % saline; filter if fractional doses (< 300 mg) are required.

Adverse Effects

• Infusion reactions: pruritus, rash, hypotension, fever (≈ 10 %).
• Infections: upper respiratory tract infections, urinary tract infections; reactivation of latent infections (JC virus, HBV).
• PML: 5–30 % in JCV‑positive patients after 1 year; mortality 25–50 %.
• Dermatologic: eczema, skin infections.
• Lab abnormalities: mild eosinophilia, transient IVIG‑like spikes.
• Serious: neoplastic disease (rare), hypersensitivity reactions (anaphylaxis).

Monitoring

• JC virus PCR: baseline, every 3 months for first 2 years, then every 6 months if positive.
• Neurologic assessment: EDSS score, MRI of brain/spine at baseline, 6 months, then annually.
• CBC & CMP: every 3 months to detect hematologic or hepatic toxicity.
• Pregnancy test: before initiating therapy; repeated if pregnancy suspected.
• Infusion‑related precautions: pulse oximetry, BP monitoring during infusion.

Clinical Pearls

• PML early‑warning: A single MRI lesion with T2‑bright flare in a JCV‑positive patient is the most sensitive early indicator—urgent drug cessation and MRI follow‑up needed.
• Infusion technique: Splitting the 300 mg dose into two 150 mg aliquots during the first infusion may reduce incidence of Grade 3 reactions.
• Drug interactions: No clinically relevant interactions; however, concomitant immunosuppressants (e.g., rituximab, mycophenolate) amplify PML risk.
• Re‑initiation: Once natalizumab is stopped, a 4‑month wash‑out period is recommended before starting another anti‑integrin therapy or switching to fingolimod to minimize overlapping immune suppression.
• Pregnancy: Use Tysabri only in the last trimester if disease relapse risk outweighs teratogenic risk; consider wash‑out and switch to interferon-β or glatiramer acetate.

Key takeaway: Natalizumab’s potent anti‑inflammatory effect is counterbalanced by a pronounced PML risk profile that necessitates rigorous screening and serial monitoring. High‑yield surveillance for JC‑virus and MRI changes should guide therapy duration decisions.