Introduction
Darunavir (brand name Prezista) is a second-generation protease inhibitor antiretroviral medication used primarily in the treatment of human immunodeficiency virus (HIV-1) infection. It was approved by the FDA in 2006 and represents a significant advancement in HIV therapy due to its high genetic barrier to resistance and efficacy against multidrug-resistant HIV strains. Darunavir is always administered with a pharmacokinetic enhancer (ritonavir or cobicistat) to boost its plasma concentrations.
Mechanism of Action
Darunavir selectively inhibits HIV-1 protease, an enzyme required for proteolytic cleavage of viral polyprotein precursors into functional proteins in HIV-infected cells. By preventing this cleavage, darunavir leads to the production of immature, non-infectious viral particles. The drug demonstrates potent activity against both wild-type HIV and strains that are resistant to other protease inhibitors.
Indications
- Treatment of HIV-1 infection in combination with other antiretroviral agents in treatment-naïve and treatment-experienced adults and pediatric patients (3 years and older)
- Post-exposure prophylaxis (off-label use in combination with other antiretrovirals)
- Darunavir is always used as part of combination antiretroviral therapy and should never be used as monotherapy
Dosage and Administration
Adults:- Treatment-naïve or treatment-experienced without darunavir resistance mutations: 800 mg once daily with ritonavir 100 mg once daily or cobicistat 150 mg once daily
- Treatment-experienced with darunavir resistance mutations: 600 mg twice daily with ritonavir 100 mg twice daily
- Dosing based on body weight and must be co-administered with ritonavir
- Consult specific pediatric dosing guidelines
- Must be taken with food to enhance bioavailability
- Tablets should be swallowed whole, not chewed or crushed
- Dosage adjustment required in patients with hepatic impairment
Pharmacokinetics
Absorption: Peak plasma concentrations achieved 2.5-4 hours after administration. Bioavailability increases approximately 30% when taken with food. Distribution: Protein binding is approximately 95%, primarily to alpha-1-acid glycoprotein. Apparent volume of distribution is 131-155 L. Metabolism: Primarily metabolized by cytochrome P450 3A4 enzymes. Ritonavir or cobicistat co-administration inhibits CYP3A4, increasing darunavir exposure. Elimination: Terminal half-life is approximately 15 hours when co-administered with ritonavir. Primarily excreted in feces (79.5%) and urine (13.9%).Contraindications
- Known hypersensitivity to darunavir or any component of the formulation
- Concomitant use with drugs highly dependent on CYP3A4 for clearance and with narrow therapeutic indices (alfuzosin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, lovastatin, simvastatin, sildenafil for pulmonary hypertension, triazolam, oral midazolam)
- Concomitant use with strong CYP3A inducers (rifampin, St. John's wort)
Warnings and Precautions
Hepatotoxicity: Severe hepatotoxicity has been reported. Monitor hepatic function before and during therapy. Skin reactions: Severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Discontinue therapy if severe reactions occur. Drug interactions: Potential for serious and/or life-threatening interactions. Review complete medication profile including over-the-counter and herbal products. Fat redistribution: Redistribution/accumulation of body fat has been observed with protease inhibitor therapy. Immune reconstitution syndrome: Inflammatory response to opportunistic infections may occur during initial treatment. Hemophilia: Increased bleeding has been reported in patients with hemophilia.Drug Interactions
Significant interactions include:- Anticonvulsants: Carbamazepine, phenobarbital, phenytoin (reduce darunavir levels)
- Antimycobacterials: Rifampin, rifapentine (contraindicated)
- Ergot derivatives: Contraindicated
- GI motility agents: Cisapride (contraindicated)
- Neuroleptics: Pimozide (contraindicated)
- PDE5 inhibitors: Dose adjustment required
- Sedatives/hypnotics: Triazolam, oral midazolam (contraindicated)
- Statins: Lovastatin, simvastatin (contraindicated); use lowest dose of atorvastatin or rosuvastatin
- Warfarin: Monitor INR closely
Adverse Effects
Common (≥10%): Diarrhea, nausea, headache, rash Less common (1-10%): Vomiting, abdominal pain, fatigue, insomnia, increased triglycerides, increased LDL cholesterol Serious adverse effects:- Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
- Hepatotoxicity
- Hyperglycemia/diabetes mellitus
- Fat redistribution
- Immune reconstitution syndrome
- Hemophilia-related bleeding
Monitoring Parameters
- HIV viral load and CD4 count at baseline and regularly during therapy
- Liver function tests at baseline and during therapy
- Fasting lipid panel at baseline and periodically during treatment
- Blood glucose monitoring
- Signs and symptoms of infection (immune reconstitution syndrome)
- Skin reactions, especially during initial weeks of therapy
- Pregnancy testing in women of childbearing potential
Patient Education
- Take darunavir exactly as prescribed with food
- Never miss doses to maintain effective viral suppression
- Always take with ritonavir or cobicistat as directed
- Inform all healthcare providers about all medications being taken
- Report any signs of liver problems (jaundice, dark urine, light-colored stools)
- Report any skin rash or allergic reactions immediately
- Use effective contraception; darunavir may reduce effectiveness of hormonal contraceptives
- Darunavir does not cure HIV or prevent transmission to others
- Continue practicing safe sex and using precautions to prevent transmission
- Store medication at room temperature in original container
References
1. FDA Prescribing Information: Prezista (darunavir) tablets. [Revised January 2023] 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. 3. Molina JM, et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced patients: week 48 results of the POWER 3. J Acquir Immune Defic Syndr. 2007;46(1):24-31. 4. Clotet B, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369(9568):1169-1178. 5. Orkin C, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2013;14(1):49-59. 6. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2023. Darunavir.