Ritonavir

Ritonavir is an oral protease inhibitor that is now used almost entirely at low dose as a pharmacokinetic booster for other protease inhibitors and for nirmatrelvir. It is a strong inhibitor of CYP3A4 and an inducer of other enzymes, so it brings a very large list of drug interactions, which is its main hazard. Full-dose ritonavir as an antiviral is no longer used because of intolerance.

Class. HIV protease inhibitor; pharmacokinetic booster.

Mechanism. Inhibits HIV protease at high dose. At low dose it inhibits CYP3A4 (mechanism-based) and P-glycoprotein, raising levels of co-administered drugs. It induces CYP1A2, CYP2C9, CYP2C19 and UGT enzymes.

Pharmacokinetics. Absorption increased by food. Half life 3 to 5 hours. Metabolised by CYP3A4 and CYP2D6. Highly protein bound.

Boosting darunavir (adults). 100 mg orally once daily with darunavir 800 mg, or twice daily with darunavir 600 mg.

Boosting atazanavir (adults). 100 mg once daily with atazanavir 300 mg.

Boosting lopinavir. Given in the fixed combination; extra ritonavir is added with rifampicin.

COVID-19 (with nirmatrelvir). Ritonavir 100 mg twice daily with nirmatrelvir 300 mg for 5 days.

Children. Boosting doses are weight-banded and specialist-led.

Loading dose, maintenance dose and titration. Not applicable at booster doses. Maximum: 200 mg daily as a booster; 1200 mg daily as the older full dose.

Main alternative. Cobicistat as a booster.

Contraindications. Hypersensitivity; co-administration with the following drugs: amiodarone, dronedarone, flecainide, propafenone, quinidine, ranolazine, lovastatin, simvastatin, lurasidone, pimozide, ergot alkaloids, oral midazolam, triazolam, sildenafil for pulmonary hypertension, colchicine in kidney or liver impairment, and strong inducers (carbamazepine, phenytoin, phenobarbital, rifampicin, St John’s wort).

Serious adverse effects. Hepatotoxicity, pancreatitis, QT and PR prolongation, severe skin reactions, hyperglycaemia and diabetes, and adrenal suppression with Cushing syndrome when given with inhaled or injected corticosteroids.

Common adverse effects. Nausea, diarrhoea, taste disturbance, perioral paraesthesia, and raised triglycerides and cholesterol.

Interactions. - Anticoagulants: avoid rivaroxaban and apixaban at high dose; monitor warfarin. - Atorvastatin and rosuvastatin: use the lowest dose or withhold. - Immunosuppressants (tacrolimus, ciclosporin, sirolimus) rise greatly: specialist-led reduction. - Hormonal contraceptives, methadone and some anticonvulsants are lowered. - Rifabutin: reduce the dose to 150 mg every other day or three times weekly.

Common prescribing errors. Prescribing without a full drug history, forgetting inhaled corticosteroids, and giving a statin at full dose.

Special groups. - Pregnancy: used widely as a booster. - Breastfeeding: compatible. - Children: oral solution and powder have alcohol and need care in neonates. - Older adults: high interaction burden. - Kidney impairment: no adjustment. - Liver impairment: avoid in decompensated disease.

Regional points. In East Africa it is almost always taken inside heat-stable fixed-dose tablets; it is a major interaction hazard when patients also take medicines from private pharmacies or herbal sources.

Formulations. Tablets 100 mg (heat-stable); oral solution 80 mg/mL; powder 100 mg sachet.

Administration. Tablets swallowed whole with food; given at the same time as the boosted drug.

Baseline. Full drug history including herbal products and inhaled steroids, liver tests, lipids, glucose, ECG if on QT drugs.

Monitoring. Liver tests at 4 and 12 weeks and then every 6 months; lipids and glucose yearly; interaction review at every prescription change.

Stopping thresholds. Stop for pancreatitis, severe skin reaction, ECG changes with symptoms, or ALT over 3 times the upper limit of normal with symptoms, or over 5 times without.

Referral and escalation. Specialist review for transplant recipients, complex drug lists and Cushing syndrome.