DARUNAVIR ETHANOLATE
Clinical safety rating: safe
Strong CYP3A4 inducers (eg rifampin) are contraindicated as they significantly decrease levels May cause severe skin reactions and hepatotoxicity.
Darunavir is an HIV-1 protease inhibitor that selectively inhibits the cleavage of HIV-encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature infectious virus particles.
| Metabolism | Primarily metabolized by CYP3A isoenzymes; coadministration with strong CYP3A inhibitors (e.g., ritonavir, cobicistat) is required to boost systemic exposure. |
| Excretion | Primarily hepatic metabolism via CYP3A4, followed by biliary excretion of metabolites; renal excretion of unchanged drug is minimal (<10%). In feces, approximately 79% of dose is recovered as metabolites; in urine, <10% as unchanged drug. |
| Half-life | Terminal elimination half-life is approximately 15 hours when coadministered with ritonavir (100 mg), and about 5-6 hours without booster. Clinical context: allows once-daily or twice-daily dosing with boosting. |
| Protein binding | Approximately 95% bound to plasma proteins (primarily alpha-1-acid glycoprotein). |
| Volume of Distribution | Volume of distribution is 0.2-0.3 L/kg (approximately 15-20 L), indicating distribution into total body water and tissues. |
| Bioavailability | Oral bioavailability is approximately 37% (unboosted) but increases to 50-70% when administered with ritonavir or cobicistat. Bioavailability is enhanced when taken with food. |
| Onset of Action | Oral administration: therapeutic concentrations achieved within 2-4 hours; time to maximum plasma concentration (Tmax) is 2.5-4 hours. No parenteral route available. |
| Duration of Action | With ritonavir boosting, duration of action is approximately 24 hours, supporting once-daily dosing (600/100 mg twice daily or 800/100 mg once daily). Without booster, duration is shorter (8-12 hours). |
600 mg orally twice daily with ritonavir 100 mg twice daily, or 800 mg orally once daily with ritonavir 100 mg once daily and with food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥15 mL/min. For GFR <15 mL/min, use with caution; no specific dose recommendation due to lack of data. |
| Liver impairment | Child-Pugh A: No dose adjustment. Child-Pugh B: Use with caution; no specific dose adjustment recommended. Child-Pugh C: Not recommended. |
| Pediatric use | Age ≥3 years and weight ≥10 kg: based on weight: 10 to <15 kg: 600 mg/100 mg twice daily; 15 to <30 kg: 675 mg/100 mg twice daily; 30 to <40 kg: 750 mg/100 mg twice daily; ≥40 kg: 600 mg/100 mg twice daily. All doses with ritonavir and with food. |
| Geriatric use | No specific dose adjustments recommended; use standard adult dosing with monitoring for increased adverse effects due to age-related comorbidities and polypharmacy. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inducers (eg rifampin) are contraindicated as they significantly decrease levels May cause severe skin reactions and hepatotoxicity.
| FDA category | Animal |
| Breastfeeding | Darunavir is excreted in human breast milk at low concentrations. Milk-to-plasma ratio is approximately 0.1. In combination with ritonavir, infant exposure is estimated to be <1% of maternal weight-adjusted dose. However, guidelines recommend avoiding breastfeeding in HIV-infected women to prevent postnatal transmission. |
| Teratogenic Risk |
■ FDA Black Box Warning
None
| Common Effects | Nausea |
| Serious Effects |
["Co-administration with drugs highly dependent on CYP3A for clearance (e.g., alfuzosin, amiodarone, quinidine, ergot derivatives, midazolam, triazolam, lovastatin, simvastatin, sildenafil for pulmonary hypertension)","Severe hepatic impairment (Child-Pugh class C)"]
| Precautions | ["Hepatotoxicity (including acute hepatitis and hepatic decompensation) reported, especially in patients with pre-existing hepatic impairment or coinfection with hepatitis B or C","Severe skin reactions (e.g., Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms)","Sulfonamide allergy: darunavir contains a sulfonamide moiety; use with caution in patients with known sulfonamide allergy","Increased risk of bleeding in patients with hemophilia","Fat redistribution and metabolic changes (e.g., hyperlipidemia, insulin resistance)","Immune reconstitution syndrome"] |
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| Darunavir ethanolate is not associated with increased risk of major birth defects. First trimester: No increased risk based on data from the Antiretroviral Pregnancy Registry. Second and third trimesters: No evidence of fetal toxicity. However, hyperbilirubinemia and kernicterus are theoretical risks based on high protein binding and bilirubin displacement. |
| Fetal Monitoring | Monitor maternal HIV viral load and CD4+ count regularly. Assess liver function tests due to risk of hepatotoxicity. In third trimester, monitor for hyperbilirubinemia in the neonate if maternal bilirubin is elevated. No specific fetal monitoring required beyond routine prenatal care. |
| Fertility Effects | No evidence that darunavir ethanolate impairs fertility in males or females. In animal studies, no adverse effects on mating or fertility were observed at systemic exposures equivalent to human therapeutic doses. |