Ustekinumab for Inflammatory Bowel Disease

Ustekinumab is a human monoclonal antibody against the p40 subunit shared by interleukin 12 and interleukin 23. It is used for moderate to severe Crohn disease and ulcerative colitis after conventional treatment or anti-TNF therapy has failed. Its safety record is favourable.

Classification. Biologic; interleukin 12 and 23 inhibitor.

Mechanism. Binds the p40 subunit of interleukin 12 and interleukin 23, preventing their binding to receptors on T cells and natural killer cells, and reducing inflammatory Th1 and Th17 pathways.

Pharmacodynamics. Intravenous induction gives response within 2 to 8 weeks. Maximum effect at 16 weeks.

Pharmacokinetics. Half-life about 3 weeks. Subcutaneous bioavailability about 57%. Clearance is higher with high weight and anti-drug antibodies.

Metabolism. Proteolytic catabolism.

Adult doses.

Crohn disease and ulcerative colitis, moderate to severe.

• Induction: single intravenous dose by weight:

- 55 kg or less: 260 mg.

- Over 55 kg to 85 kg: 390 mg.

- Over 85 kg: 520 mg.

• Maintenance: 90 mg subcutaneously 8 weeks after the intravenous dose, then every 12 weeks.

• If response is partial or lost, give 90 mg every 8 weeks.

• Stop if there is no response by 16 weeks.

Children. Limited data; specialist use only in some markets (Crohn disease from 40 kg).

Kidney and liver adjustment. None.

Contraindications. Clinically important active infection (including active tuberculosis); hypersensitivity.

Common adverse effects. Nasopharyngitis, headache, fatigue, injection site reactions, nausea and arthralgia.

Serious adverse effects.

• Serious infections (tuberculosis, salmonellosis, and opportunistic infection in patients with genetic susceptibility).

• Hypersensitivity and anaphylaxis (rare).

• Non-melanoma skin cancer.

• Reversible posterior leukoencephalopathy syndrome (rare).

• Interstitial pneumonia (rare).

Major interactions.

• Live vaccines: avoid during and for 15 weeks after treatment.

• Other biologics: avoid combination.

• Immunosuppressants: additive infection risk.

• Warfarin and ciclosporin: monitor, as inflammation changes drug handling.

Special groups.

• Pregnancy: limited data; low placental transfer early; continue if needed to control disease.

• Breastfeeding: low milk levels; compatible.

• Children: limited data.

• Older adults: no adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment.

• Regional: limited availability and high cost in East Africa; biosimilars are lowering costs; tuberculosis screening is needed.

Formulations. Intravenous vial 130 mg in 26 mL; subcutaneous prefilled syringe or pen 45 mg and 90 mg; biosimilars.

Administration.

• Dilute the intravenous dose in 250 mL of 0.9% sodium chloride and infuse over at least 1 hour through a low protein-binding 0.2 micron filter.

• Subcutaneous: inject in the thigh, abdomen or upper arm; rotate sites; patients can self-inject after training.

• Store at 2 to 8 degrees Celsius; do not shake.

Baseline. Tuberculosis screening, hepatitis B, full blood count, liver tests, pregnancy test and vaccination review.

Monitoring.

• Infection signs, injection site reactions and skin changes.

• Full blood count and liver tests every 3 to 6 months.

• Response at 16 weeks by symptoms, faecal calprotectin and endoscopy.

• Annual skin examination.

Therapeutic drug monitoring. Trough levels are used by some centres; targets are not well defined.

Stopping. Stop for serious infection, anaphylaxis, malignancy or no response at 16 weeks.

Referral and escalation. Specialist gastroenterology care throughout. Consider vedolizumab, tofacitinib or surgery if there is no response.