LOPINAVIR AND RITONAVIR
Clinical safety rating: safe
A strong inhibitor of CYP3A4 affecting many drugs Can cause GI intolerance hepatotoxicity and pancreatitis.
Lopinavir is a HIV-1 protease inhibitor that prevents cleavage of viral Gag-Pol polyproteins, resulting in immature, non-infectious viral particles. Ritonavir is a potent CYP3A4 inhibitor that increases lopinavir plasma concentrations; at subtherapeutic doses, it also inhibits HIV-1 protease.
| Metabolism | Lopinavir: primarily metabolized by CYP3A4; Ritonavir: metabolized by CYP3A4 and CYP2D6; both are substrates of CYP3A4 |
| Excretion | Lopinavir is primarily eliminated via hepatic metabolism (CYP3A4), with <3% excreted unchanged in urine and ~20% excreted unchanged in feces. Ritonavir is also predominantly hepatically metabolized, with <3.5% excreted unchanged in urine and ~86% eliminated in feces (mostly as metabolites). |
| Half-life | Lopinavir terminal elimination half-life is approximately 5–6 hours (range 4–8 h) when co-administered with ritonavir. Ritonavir half-life is about 3–5 hours. The prolonged half-life of lopinavir in the presence of ritonavir supports twice-daily dosing; steady state is reached within 2–3 days. |
| Protein binding | Lopinavir is 98–99% bound to plasma proteins, primarily alpha-1-acid glycoprotein and albumin. Ritonavir is also 98–99% bound, mainly to albumin and alpha-1-acid glycoprotein. High protein binding may affect distribution and drug interactions. |
| Volume of Distribution | Lopinavir apparent volume of distribution (Vd/F) is approximately 0.5–0.6 L/kg (about 30–40 L total), indicating moderate tissue distribution. Ritonavir Vd/F is about 0.4–0.6 L/kg. The Vd is not significantly affected by weight, suggesting extensive protein binding. |
| Bioavailability | Lopinavir bioavailability is approximately 30–40% when co-formulated with ritonavir as a tablet or oral solution. Ritonavir bioavailability is about 60–80%. The combination is not administered parentally; oral bioavailability is enhanced by food (tablet: increased by ~20–30%; solution: high-fat meal increases absorption). |
| Onset of Action | Oral administration: Antiviral activity begins within hours of first dose, with maximal viral load reduction observed after 2–4 weeks of continuous therapy. There is no intravenous formulation; oral onset is not immediate. |
| Duration of Action | Lopinavir/ritonavir (400/100 mg twice daily) maintains therapeutic plasma concentrations above the IC50 for HIV-1 over the 12-hour dosing interval. Clinical effect persists with adherence; missed doses lead to rapid viral rebound within days. |
Lopinavir/ritonavir 400/100 mg (two tablets of 200/50 mg or 5 mL oral solution 80/20 mg per mL) orally twice daily with food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for renal impairment. Not significantly removed by hemodialysis. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25% (e.g., 400/100 mg once daily or 200/50 mg twice daily); Child-Pugh C: contraindicated. |
| Pediatric use | Weight-based dosing for oral solution: 14 days to <1 year: 300/75 mg/m² twice daily; >1 year to <18 years: weight <15 kg: 12/3 mg/kg twice daily; 15-40 kg: 10/2.5 mg/kg twice daily; >40 kg: adult dose (400/100 mg twice daily). Tablets: weight ≥15 kg: 100/25 mg twice daily; ≥25 kg: 200/50 mg twice daily; ≥40 kg: 400/100 mg twice daily. |
| Geriatric use | No specific dose adjustment based solely on age. Use with caution due to increased risk of comorbidities and potential drug interactions; monitor renal function and hepatic function closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
A strong inhibitor of CYP3A4 affecting many drugs Can cause GI intolerance hepatotoxicity and pancreatitis.
| FDA category | Animal |
| Breastfeeding | Lopinavir and ritonavir are present in human breast milk at low concentrations. The milk-to-plasma (M/P) ratio for lopinavir is approximately 0.1-0.3. The estimated infant daily dose from milk is less than 1% of the maternal therapeutic dose, which is unlikely to cause adverse effects. However, due to the risk of HIV transmission through breastfeeding, mothers with HIV should not breastfeed. For other indications (e.g., COVID-19, though not standard), the benefits of breastfeeding should be weighed against potential risks. |
■ FDA Black Box Warning
None
| Common Effects | Nausea |
| Serious Effects |
["Hypersensitivity to lopinavir, ritonavir, or any component","Concomitant use with drugs highly dependent on CYP3A4 clearance (e.g., alfuzosin, amiodarone, dronedarone, colchicine in renal/hepatic impairment, ergot derivatives, lovastatin, simvastatin, midazolam, triazolam, lurasidone, pimozide, quetiapine, ranolazine, sildenafil [for pulmonary arterial hypertension], St. John's wort, etc.)","Severe hepatic impairment (Child-Pugh class C)"]
| Precautions | ["Hepatotoxicity: may cause elevations in transaminases; avoid in patients with severe hepatic impairment","Pancreatitis: cases reported, especially in patients with hypertriglyceridemia or prior pancreatitis","Cardiac effects: PR interval prolongation; caution with pre-existing conduction abnormalities or concurrent use of PR-prolonging drugs","QT prolongation: limited data; monitor if used with other QT-prolonging agents","Lipid abnormalities: increases in total cholesterol and triglycerides","Insulin resistance/diabetes: new-onset or exacerbation reported","Hemophilia: increased bleeding in patients with hemophilia A or B","Immune reconstitution syndrome","Fat redistribution: accumulation of central fat, dorsocervical fat pad, peripheral wasting","Osteonecrosis: cases reported, especially in advanced HIV disease or long-term combination therapy","Drug interactions: contraindicated with drugs highly dependent on CYP3A4 clearance (e.g., midazolam, triazolam, ergot alkaloids, etc.)"] |
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| Teratogenic Risk | Lopinavir/ritonavir is not associated with a significant increase in major birth defects. First trimester exposure data from the Antiretroviral Pregnancy Registry do not indicate an elevated risk of teratogenicity compared to the background rate. However, there is a theoretical risk based on animal studies showing embryotoxicity at high doses. Second and third trimester use has not been linked to specific fetal adverse effects, though late pregnancy exposure may be associated with transient metabolic disturbances in the neonate, including hyperbilirubinemia and hypoglycemia. |
| Fetal Monitoring | Monitor maternal liver function tests (ALT, AST) and renal function periodically due to potential hepatotoxicity and renal effects. Assess glucose tolerance for hyperglycemia/diabetes as lopinavir/ritonavir may cause insulin resistance. In late pregnancy, monitor fetal growth via ultrasound (risk of preterm birth or low birth weight reported in some studies). Postnatally, assess neonate for hyperbilirubinemia and hypoglycemia if exposed near term. |
| Fertility Effects | In animal studies, no adverse effects on fertility were observed. Human data are limited, but lopinavir/ritonavir is not known to impair male or female fertility. However, hormonal contraceptives may be less effective due to enzyme induction; alternative or additional contraceptive methods should be used. |