Ritonavir

It is no longer used as a single protease inhibitor but, instead, is used as a pharmacokinetic enhancer or "booster” of other protease inhibitors. Ritonavir is a potent inhibitor of CYP3A, and concomitant ritonavir administration (at low doses) increases the bioavailability of the second protease inhibitor, often allowing for longer dosing intervals. The resulting higher Cmin levels of the “boosted" protease inhibitors also help to prevent the development of resistance. Therefore, “boosted" protease inhibitors are preferred agents in the DHHS treatment guidelines. Metabolism and biliary excretion are the primary methods of elimination. Ritonavir has a half-life of 3 to 5 hours. Because it is primarily an inhibitor of CYP450 isozymes, numerous drug interactions have been identifi ed. Nausea, vomiting, diarrhea,headache, and circumoral paresthesias are among the more common adverse effects.elevations of hepatic aminotransferases and triglycerides in the plasma also occur. Drugs that increase the activity of the cytochrome P450 isoform CYP3A4 (anticonvulsants, rifamycins) reduce serum levels of ritonavir, and drugs that inhibit this enzyme (azole antifungals, cimetidine, erythromycin) elevate serum levels of the antiviral drug. Ritonavir inhibits the metabolism of a wide range of drugs, including erythromycin, dronabinol, ketoconazole, prednisone, rifampin, and saquinavir. Subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of other protease inhibitors (eg, indinavir, lopinavir, saquinavir); this is the rationale for PI combinations that include ritonavir because it permits the use of lower doses of the other protease inhibitor.