Usage
Darunavir, co-administered with ritonavir, is prescribed for the treatment of Human Immunodeficiency Virus-1 (HIV-1) infection in adults and pediatric patients 3 years of age and older, in combination with other antiretroviral agents. It is classified as an antiviral drug, specifically a protease inhibitor. Darunavir inhibits the HIV-1 protease enzyme, preventing the cleavage of viral polyproteins necessary for the assembly of infectious viral particles. Ritonavir, also a protease inhibitor, acts as a pharmacokinetic enhancer by inhibiting the cytochrome P450 3A4 (CYP3A4) enzyme, which metabolizes darunavir, thereby increasing darunavir’s plasma concentration and extending its half-life.
Alternate Names
Darunavir is often referred to as DRV, while ritonavir is known as RTV. Brand names for darunavir include Prezista. A fixed-dose combination of darunavir and cobicistat is marketed as Prezcobix.
How It Works
Pharmacodynamics: Darunavir binds to the active site of the HIV-1 protease enzyme, preventing its dimerization and catalytic activity. This inhibition blocks the processing of viral polyproteins, resulting in the formation of immature, non-infectious viral particles. Ritonavir boosts the concentration of darunavir by inhibiting CYP3A4, the primary enzyme responsible for darunavir metabolism.
Pharmacokinetics: Darunavir is administered orally and should be taken with food to enhance absorption. Ritonavir significantly increases darunavir’s bioavailability. Darunavir is primarily metabolized by CYP3A4 in the liver, and its metabolites are excreted in the feces and urine. Ritonavir’s inhibition of CYP3A4 extends darunavir’s elimination half-life to approximately 15 hours.
Mode of Action: Darunavir acts by competitive inhibition of the HIV-1 protease enzyme. It binds directly to the active site of the protease, preventing the enzyme from cleaving viral polyprotein precursors, which are essential for the production of mature, infectious virions.
Elimination Pathways: Darunavir is predominantly metabolized in the liver by CYP3A4 enzymes. The resulting metabolites are mainly excreted in the feces, with a smaller portion eliminated in the urine.
Dosage
Standard Dosage
Adults:
- Treatment-naïve or Treatment-experienced (no darunavir resistance-associated substitutions): 800 mg darunavir with 100 mg ritonavir once daily, taken with food.
- Treatment-experienced (with at least one darunavir resistance-associated substitution): 600 mg darunavir with 100 mg ritonavir twice daily, taken with food.
Children (3 to <18 years and ≥10 kg):
Dosage is based on body weight and must be determined by a physician. Dosing charts based on weight and treatment experience are available in prescribing information. Darunavir should be taken with ritonavir and with food.
Special Cases:
- Elderly Patients: Caution should be exercised due to potential age-related decreases in hepatic, renal, or cardiac function, and increased likelihood of concomitant diseases and drug therapies. Dosage adjustments may be necessary.
- Patients with Renal Impairment: No dosage adjustment is recommended for mild to moderate renal impairment. Data is limited for severe renal impairment.
- Patients with Hepatic Dysfunction: No dosage adjustment is required for mild to moderate hepatic impairment. Darunavir/ritonavir is not recommended for patients with severe hepatic impairment (Child-Pugh Class C).
- Patients with Comorbid Conditions: Close monitoring and potential dose adjustments may be required based on specific comorbid conditions.
Clinical Use Cases
Darunavir/ritonavir is not specifically indicated for use in clinical scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary indication is for the treatment of chronic HIV-1 infection.
Dosage Adjustments
Dose modifications may be required based on drug-drug interactions, treatment history, genotypic/phenotypic testing results, and individual patient tolerance.
Side Effects
Common Side Effects:
Diarrhea, nausea, vomiting, headache, rash, abdominal pain, elevated liver enzymes.
Rare but Serious Side Effects:
Drug-induced hepatitis, severe skin reactions (Stevens-Johnson Syndrome), pancreatitis, allergic reactions, new or worsening kidney problems, changes in heart rhythm (QT prolongation), diabetes, immune reconstitution inflammatory syndrome (IRIS).
Long-Term Effects:
Hyperlipidemia, lipodystrophy, increased risk of cardiovascular disease, diabetes, and kidney disease.
Adverse Drug Reactions (ADR):
Severe skin reactions, hepatotoxicity, pancreatitis, hypersensitivity reactions.
Contraindications
- Severe hepatic impairment (Child-Pugh Class C)
- Hypersensitivity to darunavir, ritonavir, or any component of the formulation.
- Co-administration with drugs highly dependent on CYP3A for clearance and with a narrow therapeutic index (e.g., alfuzosin, amiodarone, astemizole, cisapride, pimozide, quetiapine, rifampin, St. John’s wort, triazolam, midazolam).
Drug Interactions
Darunavir and ritonavir are both substrates and inhibitors of CYP3A4 and can interact with numerous medications. Clinically significant interactions can occur with antiarrhythmics, anticonvulsants, antifungals, antimycobacterials, HMG-CoA reductase inhibitors, immunosuppressants, sedatives, and others. Consult a drug interaction resource for a comprehensive list.
Pregnancy and Breastfeeding
Darunavir/ritonavir is generally considered safe during pregnancy. However, due to lower drug exposures during pregnancy, the twice-daily regimen (600 mg darunavir/100 mg ritonavir twice daily) is generally recommended. The once-daily regimen may be considered in patients with suppressed viral loads and concerns about adherence with twice-daily dosing. Breastfeeding is not recommended for women with HIV due to the risk of HIV transmission to the infant.
Drug Profile Summary
- Mechanism of Action: HIV-1 protease inhibitor; Ritonavir boosts darunavir levels by inhibiting CYP3A4.
- Side Effects: Diarrhea, nausea, vomiting, headache, rash, abdominal pain, hepatotoxicity, severe skin reactions, pancreatitis.
- Contraindications: Severe hepatic impairment, hypersensitivity, co-administration with CYP3A substrates with narrow therapeutic index.
- Drug Interactions: Numerous; consult drug interaction resources.
- Pregnancy & Breastfeeding: Generally safe in pregnancy, but twice-daily dosing preferred; breastfeeding not recommended.
- Dosage: See detailed dosage guidelines above.
- Monitoring Parameters: Liver function tests, lipid profile, blood glucose, viral load, CD4 count.
Popular Combinations
Darunavir/ritonavir is often used in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) as part of a complete antiretroviral regimen.
Precautions
Screen for hepatic dysfunction, diabetes, bleeding disorders, lipid abnormalities, and sulfa allergy before initiating treatment. Close monitoring of liver function is recommended, especially during the first few months of treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Darunavir + Ritonavir?
A: See detailed dosage guidelines above for specific recommendations for adults, children, and special populations.
Q2: What are the most common side effects of Darunavir + Ritonavir?
A: The most common side effects are diarrhea, nausea, vomiting, headache, rash, and abdominal pain.
Q3: Are there any contraindications to using Darunavir + Ritonavir?
A: Yes, contraindications include severe hepatic impairment, hypersensitivity to the drugs, and co-administration with certain medications metabolized by CYP3A4.
Q4: How should Darunavir + Ritonavir be taken?
A: Darunavir + Ritonavir should be taken orally with food to enhance absorption.
Q5: Can Darunavir + Ritonavir be used during pregnancy?
A: Yes, but the twice-daily regimen (600/100 mg twice daily) is generally preferred. Consult guidelines for individualized recommendations.
Q6: Is it safe to breastfeed while taking Darunavir + Ritonavir?
A: Breastfeeding is not recommended for HIV-positive women due to the risk of transmission.
Q7: What are the potential long-term effects of Darunavir + Ritonavir?
A: Potential long-term effects include hyperlipidemia, lipodystrophy, and increased risk of cardiovascular disease, diabetes, and kidney disease.
Q8: Does Darunavir + Ritonavir cure HIV?
A: No, Darunavir + Ritonavir does not cure HIV. It helps to control the virus and slow the progression of the disease.
Q9: What should I do if I miss a dose of Darunavir + Ritonavir?
A: Take the missed dose as soon as you remember, unless it is close to the time of your next dose. Do not double the dose.
