DARUNAVIR AND RITONAVIR
Clinical safety rating: safe
A strong inhibitor of CYP3A4 affecting many drugs Can cause GI intolerance hepatotoxicity and pancreatitis.
Darunavir is a protease inhibitor that binds to the HIV-1 protease active site, preventing cleavage of viral polyproteins into functional proteins, leading to immature, non-infectious virions. Ritonavir is a potent CYP3A4 inhibitor that increases darunavir plasma concentrations by inhibiting its metabolism.
| Metabolism | Darunavir is metabolized primarily by CYP3A4. Ritonavir is metabolized by CYP3A4 and CYP2D6; it is a strong CYP3A4 inhibitor. |
| Excretion | Darunavir: 79.5% fecal (primarily as unchanged drug), 13.9% renal (mostly metabolites). Ritonavir: 86.4% fecal, 11.3% renal. |
| Half-life | Darunavir: ~15 hours (range 10-31 h) when boosted with ritonavir; allows once-daily dosing. Ritonavir: ~3-5 hours (administered as booster). |
| Protein binding | Darunavir: ~95% bound to alpha-1-acid glycoprotein. Ritonavir: >98% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Darunavir: Vd/F ~ 88 L (approx 1.3 L/kg for 70 kg); indicates extensive tissue penetration. Ritonavir: Vd/F ~ 20-40 L (0.3-0.6 L/kg). |
| Bioavailability | Darunavir: Oral bioavailability ~37-82% (enhanced by ritonavir via CYP3A4 inhibition); food increases absorption by ~30%. Ritonavir: Oral bioavailability ~60-80% (formulation dependent). |
| Onset of Action | Oral: Onset of antiviral effect occurs within 2-4 hours after first dose, with maximal viral load reduction observed within 10-14 days. |
| Duration of Action | Oral: With once-daily dosing (800/100 mg), therapeutic plasma concentrations maintained over 24 hours; twice-daily regimen (600/100 mg) also effective for treatment-experienced patients. |
Darunavir 800 mg orally once daily plus ritonavir 100 mg orally once daily in treatment-naïve patients. In treatment-experienced patients with at least one darunavir resistance-associated mutation, darunavir 600 mg plus ritonavir 100 mg orally twice daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for renal impairment. Darunavir and ritonavir are highly protein-bound and not significantly removed by hemodialysis. |
| Liver impairment | Child-Pugh Class A: No dose adjustment. Child-Pugh Class B: Darunavir/ritonavir is contraindicated. Child-Pugh Class C: Contraindicated. |
| Pediatric use | Children ≥3 years and weighing ≥15 kg: Darunavir 800 mg plus ritonavir 100 mg once daily if no darunavir resistance-associated mutations. For weight-based dosing: 15-<30 kg: darunavir 450 mg plus ritonavir 80 mg once daily; 30-<40 kg: darunavir 600 mg plus ritonavir 100 mg once daily; ≥40 kg: darunavir 600 mg plus ritonavir 100 mg twice daily in treatment-experienced patients. Use oral suspension as appropriate. |
| Geriatric use | No specific dose adjustment recommended; monitor renal function and comorbidities. Increased susceptibility to adverse effects like diarrhea, nausea, and hyperlipidemia. Consider drug interactions with polypharmacy. |
| 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 | Breastfeeding not recommended in HIV-infected patients due to risk of HIV transmission. Limited data: darunavir concentrations in breast milk low (M/P ratio 0.03-0.06) but ritonavir not adequately studied. Insufficient data to support safety; alternative feeding advised. |
| Teratogenic Risk | During first trimester: No increased risk of major malformations based on prospective cohort data (Antiretroviral Pregnancy Registry). Second and third trimesters: No evidence of fetal toxicity. Risk of preterm delivery or low birth weight not definitively associated. Standard dosing recommended throughout pregnancy. |
■ FDA Black Box Warning
Not applicable; no boxed warning for the combination.
| Common Effects | Nausea |
| Serious Effects |
["Concomitant use with drugs highly dependent on CYP3A4 clearance (e.g., alfuzosin, ergot derivatives, midazolam oral, pimozide, simvastatin, lovastatin, sildenafil for pulmonary arterial hypertension, St. John's wort).","Concomitant use with rifampin (rifampicin).","Severe hepatic impairment (Child-Pugh class C)."]
| Precautions | ["Hepatotoxicity: Elevated liver enzymes, hepatitis, and hepatic decompensation, especially in patients with pre-existing liver disease.","Severe skin reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS).","Sulfonamide allergy: Use caution in patients with known sulfonamide allergy due to structural similarity.","Drug-induced hepatitis: Monitor liver function before and during therapy.","Hemophilia: Risk of spontaneous bleeding in patients with hemophilia A or B.","Fat redistribution: Accumulation of visceral fat, lipoatrophy, and other metabolic changes."] |
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| Fetal Monitoring | Monitor maternal liver function tests (AST, ALT), renal function, complete blood count, and glucose (risk of hyperglycemia). Fetal monitoring with serial ultrasound for growth restriction if prolonged use. Avoid in premature infants at term due to risk of kernicterus (due to ritonavir's bilirubin displacement). |
| Fertility Effects | No evidence of adverse effects on fertility in humans. Animal studies: No impairment of fertility observed with darunavir/ritonavir at systemic exposures similar to clinical doses. |