DARUNAVIR
Clinical safety rating: safe
Animal studies have demonstrated safety
Darunavir is an HIV-1 protease inhibitor that selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in virus-infected cells, thereby preventing formation of mature infectious virions.
| Metabolism | Primarily metabolized by CYP3A isoenzymes. Ritonavir or cobicistat is used as a pharmacokinetic enhancer to increase darunavir exposure. |
| Excretion | Primarily fecal (79.5% as unchanged drug or metabolites), with renal excretion accounting for approximately 13.9% (8.9% unchanged). |
| Half-life | Terminal elimination half-life is approximately 15 hours when co-administered with low-dose ritonavir, supporting once-daily dosing. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution is about 1.23 L/kg, indicating extensive tissue penetration. |
| Bioavailability | Absolute oral bioavailability is approximately 82% when co-administered with ritonavir; absorption is enhanced by food. |
| Onset of Action | Not applicable; steady-state concentrations are achieved after approximately 4 days of oral dosing. |
| Duration of Action | With ritonavir boosting, therapeutic plasma concentrations are maintained over 24 hours, allowing once-daily administration. |
600 mg orally twice daily with ritonavir 100 mg twice daily or 800 mg orally once daily with cobicistat 150 mg once daily, taken with food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. For GFR <30 mL/min, not recommended due to lack of data; consider alternative therapy. |
| Liver impairment | Child-Pugh Class A: no dose adjustment. Child-Pugh Class B: 600 mg orally twice daily with ritonavir 100 mg twice daily (caution). Child-Pugh Class C: contraindicated. |
| Pediatric use | Weight-based dosing (with ritonavir): 3-<5 kg: 50 mg/7.5 mg twice daily; 5-<7 kg: 60 mg/9 mg twice daily; 7-<10 kg: 100 mg/15 mg twice daily; 10-<15 kg: 150 mg/22.5 mg twice daily; 15-<25 kg: 200 mg/30 mg twice daily; 25-<32 kg: 300 mg/45 mg twice daily; ≥32 kg: 600 mg/100 mg twice daily. For once-daily darunavir/cobicistat: body weight ≥40 kg: 800 mg/150 mg once daily. |
| Geriatric use | No specific dose adjustment; monitor renal function and hepatic function. Use with caution due to potential 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.
| Breastfeeding | Darunavir is excreted in human breast milk in low concentrations (M/P ratio approximately 0.3-0.4). However, due to the risk of HIV transmission via breastfeeding, HIV-infected mothers should not breastfeed in the United States and other developed countries. In resource-limited settings, the small amount in milk is unlikely to cause adverse effects in the infant, but formula feeding is preferred. |
| Teratogenic Risk | Darunavir is classified as FDA Pregnancy Category C. In first trimester, there is insufficient human data; animal studies show no teratogenicity at exposures similar to human therapeutic doses. Second and third trimesters: no increased risk of major birth defects observed in the Antiretroviral Pregnancy Registry; however, there is potential for preterm delivery and low birth weight, possibly related to underlying HIV infection. |
■ FDA Black Box Warning
None.
| Common Effects | Nausea |
| Serious Effects |
["Coadministration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious/life-threatening events (e.g., alfuzosin, amiodarone, bepridil, colchicine, dronedarone, ergot derivatives, ivabradine, lomitapide, lovastatin, lurasidone, midazolam oral, naloxegol, pimozide, ranolazine, rifampin, sildenafil for pulmonary arterial hypertension, simvastatin, St. John's wort, ticagrelor, triazolam)","Coadministration with colchicine in patients with renal or hepatic impairment","Coadministration with elbasvir/grazoprevir"]
| Precautions | ["Hepatotoxicity: Cases of drug-induced hepatitis and hepatic decompensation reported, including fatalities. Monitor liver function tests.","Severe skin reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have occurred. Discontinue if severe rash develops.","Sulfonamide allergy: Use with caution in patients with known sulfonamide allergy due to structural similarity.","Lipodystrophy and metabolic abnormalities: Redistribution/accumulation of body fat, hyperlipidemia, and insulin resistance reported.","Immune reconstitution syndrome: May occur during initial treatment.","Hemophilia: Increased bleeding risk reported."] |
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| Fetal Monitoring | Monitor for maternal glucose intolerance, hepatic toxicity (elevated liver enzymes), and dermatologic reactions. Fetal monitoring includes ultrasound for growth restriction and assessment of preterm labor. Perform standard HIV viral load and CD4+ count monitoring throughout pregnancy. Monitor for signs of maternal anemia and lipid abnormalities. |
| Fertility Effects | No known significant adverse effects on fertility in humans. Animal studies show no impairment of mating or fertility at exposures up to 1.3 times the human AUC. In women with HIV, effective antiretroviral therapy may improve fertility by controlling viral load and reducing inflammation. |