RITONAVIR
Clinical safety rating: safe
Animal studies have demonstrated safety
Ritonavir inhibits HIV protease, preventing cleavage of viral polyprotein precursors into functional proteins, resulting in immature, non-infectious viral particles. It also inhibits CYP3A4, enhancing pharmacokinetics of other protease inhibitors.
| Metabolism | Primarily hepatic via CYP3A4 (major), CYP2D6 (minor). Ritonavir is a potent CYP3A4 inhibitor and inducer; induces its own metabolism via CYP3A4 autoinduction. |
| Excretion | Primarily hepatic metabolism (CYP3A4) with <3.5% excreted unchanged in urine; fecal elimination accounts for ~86% of the dose (mostly metabolites). |
| Half-life | Terminal elimination half-life is approximately 3-5 hours after multiple dosing; however, due to its potent CYP3A4 inhibition, the effective half-life for boosting other protease inhibitors is extended clinically. |
| Protein binding | 98-99% bound primarily to alpha-1-acid glycoprotein (AAG) and albumin. |
| Volume of Distribution | Approximately 0.41 L/kg (20-30 L in adults); distributes extensively into tissues including the CNS. |
| Bioavailability | Oral bioavailability is about 60-80% when taken with food; increased bioavailability with high-fat meal. |
| Onset of Action | Oral: Inhibitory effect on CYP3A4 occurs within 2-4 hours; antiviral effect is delayed as it requires combination therapy. |
| Duration of Action | CYP3A4 inhibition persists for 12-24 hours after a dose, supporting twice-daily dosing; antiviral duration depends on co-administered agents. |
600 mg orally twice daily (oral solution or tablets); as part of boosted protease inhibitor regimen: 100-400 mg orally once or twice daily depending on co-administered PI.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. For GFR <30 mL/min, use with caution; no specific guidelines; avoid in ESRD if possible due to lack of data. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce to 50% of normal dose; Child-Pugh C: contraindicated. |
| Pediatric use | Weight-based: 16 to <25 kg: 300 mg/m2 orally twice daily; 25 to <35 kg: 400 mg/m2 orally twice daily; ≥35 kg: 600 mg orally twice daily. Maximum dose: 600 mg twice daily. |
| Geriatric use | No specific dose adjustment; monitor renal and hepatic function; increased risk of QT prolongation and drug interactions; consider reduced starting dose if comorbidities. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
A strong inhibitor of CYP3A4 affecting many drugs Can cause GI intolerance hepatotoxicity and pancreatitis.
| Breastfeeding | Ritonavir is excreted in human breast milk at low levels; estimated infant dose is <2% of maternal weight-adjusted dose. M/P ratio is approximately 0.3-0.5. Limited data suggest no adverse effects in breastfed infants. However, HIV transmission via breast milk is a contraindication in high-resource settings. |
| Teratogenic Risk | In first trimester, limited human data show no significant increase in major malformations above baseline; however, cases of preterm delivery, low birth weight, and stillbirth have been reported. In second and third trimesters, risk of hyperbilirubinemia and lactic acidosis in neonates. Animal studies show no teratogenicity at clinically relevant doses. |
■ FDA Black Box Warning
None explicitly required by FDA; however, use with caution in patients with hepatic impairment due to risk of hepatotoxicity.
| Common Effects | Nausea |
| Serious Effects |
["Concurrent use with drugs highly dependent on CYP3A4 for clearance (e.g., alfuzosin, cisapride, ergot derivatives, lovastatin, midazolam, pimozide, simvastatin, triazolam)","Concurrent use with St. John's wort (reduces ritonavir efficacy)","Severe hepatic impairment (Child-Pugh Class C)"]
| Precautions | ["Hepatotoxicity (including fatalities), especially in patients with pre-existing liver disease or elevated transaminases","Hyperglycemia, new-onset diabetes, or exacerbation of pre-existing diabetes","Pancreatitis (fatal cases reported), particularly in patients with advanced HIV, hypertriglyceridemia, or prior history","PR interval prolongation and heart block (rare)","Drug interactions due to potent CYP3A4 inhibition leading to increased exposure of co-administered drugs","Lipodystrophy and metabolic abnormalities (e.g., hyperlipidemia, insulin resistance)","Immune reconstitution syndrome","Hemolytic anemia (rare)"] |
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| Fetal Monitoring | Monitor maternal liver function, renal function, glucose, lipids, and complete blood count. Fetal ultrasound for growth and anatomy. Assess for neonatal hyperbilirubinemia and lactic acidosis after delivery. Consider therapeutic drug monitoring to maintain trough concentrations >0.1 mcg/mL. |
| Fertility Effects | No known adverse effects on fertility in humans. Animal studies show no impairment. May be used in ART protocols without known negative impact on oocyte or sperm quality. |