Darunavir

Darunavir is an HIV-1 protease inhibitor (PI) with potent activity against both wild-type and PI-resistant HIV-1. It must be coadministered with a pharmacokinetic booster — either ritonavir or cobicistat — and taken with food.

Administration

• Type: HIV-1 protease inhibitor (PI)
• Dosage Forms: 75 mg, 150 mg, 300 mg, 400 mg, 600 mg, 800 mg tablets; 100 mg/mL oral suspension
• Routes of Administration: Oral
• Common Trade Names: Prezista; also in fixed-dose combination: Prezcobix (darunavir/cobicistat), Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)

Adult Dosing

Must be taken with a booster and with food:

• Treatment-naive or treatment-experienced with no darunavir resistance mutations: 800 mg + ritonavir 100 mg PO once daily
• Treatment-experienced with ≥1 darunavir resistance mutation: 600 mg + ritonavir 100 mg PO twice daily
• May substitute cobicistat 150 mg for ritonavir in once-daily regimens (not for twice-daily dosing)
• Must be taken with food (increases exposure ~30%)
• Contains a sulfonamide moiety — use with caution in sulfa-allergic patients (though cross-reactivity rate is low in clinical studies)

Pediatric Dosing

• Approved for patients ≥3 years and ≥10 kg (with ritonavir); ≥15 kg (with cobicistat)
• Weight-based dosing; consult prescribing information or pediatric ID
• Not recommended in children <3 years (toxicity and mortality observed in juvenile animal studies)

Special Populations

Pregnancy Rating

• No adequate controlled studies in pregnant women; no increased birth defect rate in registry data
• Pregnancy dosing: 600 mg/ritonavir 100 mg PO twice daily is generally recommended; once-daily 800 mg/ritonavir 100 mg may be considered only in patients already virologically suppressed on that regimen prior to pregnancy
• Do not initiate darunavir/cobicistat during pregnancy (lower darunavir exposure); switch to darunavir/ritonavir
• Antiretroviral Pregnancy Registry: 1-800-258-4263

Lactation risk

• Present in rat milk; unknown in human milk. Women with HIV should not breastfeed (risk of HIV transmission)

Renal Dosing

• Adult: No dose adjustment needed; renal clearance is minimal (~8% of dose as unchanged drug with ritonavir)
  • Not studied in severe impairment or ESRD, but unlikely removed by hemodialysis (95% protein bound)
• Pediatric: No specific data; no adjustment expected

Hepatic Dosing

• Adult: No adjustment for mild or moderate (Child-Pugh A or B) impairment; use with caution
  • Severe (Child-Pugh C): Not recommended (not studied)
• Pediatric: Not studied

Contraindications

• Allergy to class/drug
• Coadministration with drugs highly dependent on CYP3A for clearance where elevated levels cause serious/life-threatening events (e.g., alfuzosin, ergot derivatives, dronedarone, pimozide, lurasidone, oral midazolam, triazolam, rifampin, St. John's wort, simvastatin, lovastatin, sildenafil for PAH)

Adverse Reactions

Serious

• Hepatotoxicity — drug-induced hepatitis and hepatic failure (including fatalities) reported; higher risk with pre-existing hepatic disease or hepatitis B/C co-infection
• Severe skin reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis
• Immune reconstitution inflammatory syndrome (IRIS)
• New-onset or worsening diabetes mellitus/hyperglycemia (class effect of PIs); diabetic ketoacidosis reported

Common

• Diarrhea, nausea, rash, headache
• Hyperlipidemia (elevated triglycerides and cholesterol — PI class effect)
• Lipodystrophy/fat redistribution (PI class effect)
• Transaminase elevations (higher rates in hepatitis B/C co-infection: up to 7% Grade 2–4 ALT elevations)

Pharmacology

• Half-life: ~15 hours (when boosted with ritonavir)
• Metabolism: Extensively metabolized by CYP3A4; bioavailability increases from ~37% to ~82% with ritonavir boosting
• Excretion: ~79.5% feces, ~13.9% urine

Mechanism of Action

Darunavir selectively inhibits the cleavage of HIV-1 Gag-Pol polyprotein precursors by binding to the active site of HIV-1 protease. This prevents processing of viral polyproteins into functional structural proteins and enzymes, resulting in the formation of immature, non-infectious viral particles. Darunavir maintains activity against many PI-resistant HIV-1 strains due to its flexible molecular structure and tight binding to the protease active site.

Comments

• Boosting is mandatory: Darunavir without ritonavir or cobicistat has insufficient plasma levels for antiviral effect — if a patient reports not taking the booster, the regimen is functionally not working
• Strong CYP3A inhibitor: Darunavir/ritonavir (or cobicistat) significantly increases levels of many drugs metabolized by CYP3A4. This is the most important ED consideration:
  • Common ED interactions: midazolam (IV acceptable with monitoring; oral midazolam contraindicated), fentanyl (increased levels — reduce dose and monitor), colchicine (contraindicated in renal/hepatic impairment; reduce dose otherwise), simvastatin/lovastatin (contraindicated), ergotamines (contraindicated)
• Sulfonamide moiety: Contains a sulfonamide group. In clinical trials, rash rates were similar in patients with and without sulfa allergy history. Use with caution but it is not an absolute contraindication
• Hepatitis co-infection: Monitor hepatic enzymes before initiating and at frequent intervals, especially in patients with hepatitis B/C
• Overdose: No specific antidote; supportive care. Highly protein bound; unlikely removed by dialysis

See Also

• HIV - AIDS (main)
• HIV post-exposure prophylaxis
• Immune reconstitution syndrome
• Emtricitabine/tenofovir