Protease Inhibitors

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Protease Inhibitors

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Protease Inhibitors The assembly of infectious HIV virions is dependent on an aspartate protease (HIV-1 protease) encoded by the pol gene. This viral enzyme cleaves precursor polyproteins to form the final structural proteins of the mature virion core. The HIV protease inhibitors are designer drugs based on molecular characterization of the active site of the viral enzyme. Resistance is mediated via multiple point mutations in the pol gene; the extent of cross-resistance is variable depending on the specific protease inhibitor. Protease inhibitors (PIs) have important clinical use in AIDS, most commonly in combinations with reverse transcriptase inhibitors as components of HAART. All of the PIs are substrates and inhibitors of CYP3A4 with ritonavir having the most pronounced inhibitory effect. The PIs are implicated in many drug-drug interactions with other antiretroviral agents and with commonly used medications.

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Atazanavir

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Atazanavir—This is a PI with a pharmacokinetic profile that permits once-daily dosing. Oral absorption of atazanavir requires an acidic environment—antacid ingestion should be separated by 12 h. The drug penetrates cerebrospinal and seminal fluids and undergoes biliary elimination. Adverse effects include GI distress, peripheral neuropathy, skin rash, and hyperbilirubinemia. Prolongation of the QTc interval may occur at high doses. Unlike most PIs, atazanavir does not appear to be associated with dyslipidemias, fat deposition, or a metabolic syndrome. However, it is a potent inhibitor of CYP3A4 and CYP2C9.

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Darunavir

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Darunavir—This drug is used in combination with ritonavir in treatment-experienced patients with resistance to other PIs. The drug is a substrate of CYP3A4. GI adverse effects and rash occur, and liver toxicity has been reported. Darunavir contains a sulfonamide moiety and should be used with caution in sulfonamide allergy.

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Fosamprenavir

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Fosamprenavir—Fosamprenavir is a prodrug forming amprenavir via its hydrolysis in the GI tract. The drug formulation includes propylene glycol and should not be used in children or in pregnant women. Fosamprenavir is often used in combination with low-dose ritonavir. The absorption of amprenavir is impeded by fatty foods. Amprenavir undergoes hepatic metabolism and is both an inhibitor and an inducer of CYP3A4. The drug causes GI distress, paresthesias, and rash, the latter sometimes severe enough to warrant drug discontinuation. Cross-allergenicity may occur with sulfonamides.

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Indinavir

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Indinavir—Oral bioavailability of indinavir is good except in the presence of food. Clearance is mainly via the liver, with about 10% renal excretion. Adverse effects include nausea, diarrhea, thrombocytopenia, hyperbilirubinemia, and nephrolithiasis. To reduce renal damage, it is important to maintain good hydration. Insulin resistance may be more common with indinavir than other PIs. Indinavir is a substrate for and an inhibitor of the cytochrome P450 isoform CYP3A4 and is implicated in drug interactions. Serum levels of indinavir are increased by azole antifungals and decreased by rifamycins. Indinavir increases the serum levels of antihistamines, benzodiazepines, and rifampin

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Lopinavir/ritonavir

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Lopinavir/ritonavir—In this combination, a subtherapeutic dose of ritonavir acts as a pharmacokinetic enhancer by inhibiting the CYP3A4-mediated metabolism of lopinavir. Patient compliance is improved owing to lower pill burden and the combination is usually well tolerated.

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Nelfinavir

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Nelfinavir—This PI is characterized by increased oral absorption in the presence of food, hepatic metabolism via CYP3A4 and a short half-life. As an inhibitor of drug metabolism, nelfinavir has been involved in many drug interactions. Adverse effects include diarrhea, which can be dose-limiting. The drug has the most favorable safety profile of the PIs in pregnancy.

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Ritonavir

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Ritonavir—Oral bioavailability is good, and the drug should be taken with meals. Clearance is mainly via the liver, and dosage reduction is necessary in patients with hepatic impairment. The most common adverse effects of ritonavir are GI irritation and a bitter taste. Paresthesias and 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.

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Saquinavir

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Saquinavir—Original formulations of saquinavir had low and erratic oral bioavailability. Reformulation for once-daily dosing in combination with low-dose ritonavir has improved efficacy withdecreased GI side effects. The drug undergoes extensive first-pass metabolism and functions as both a substrate and inhibitor of CYP3A4. Adverse effects of saquinavir include nausea, diarrhea, dyspepsia, and rhinitis. Saquinavir plasma levels are increased by azole antifungals, clarithromycin, grapefruit juice, indinavir, and ritonavir. Drugs that induce CYP3A4 decrease plasma levels of saquinavir.

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Tipranavir

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Tipranavir—This is a newer drug used in combination with ritonavir in treatment-experienced patients with resistance to other PIs. The drug is a substrate and inducer of CYP3A4 and also induces P-glycoprotein transporters, possibly altering GI absorption of other drugs. For example, increased blood levels of the HMG-CoA reductase inhibitors (eg, lovastatin) may occur, thus increasing the risk for myopathy and rhabdomyolysis. GI adverse effects, rash, and liver toxicity have been reported.

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Effects on carbohydrate and lipid metabolism

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Effects on carbohydrate and lipid metabolism—The use of PIs in HAART drug combinations has led to the development of disorders in carbohydrate and lipid metabolism. It has been suggested that this is due to the inhibition of lipid-regulating proteins, which have active sites with structural homology to that of HIV protease. The syndrome includes hyperglycemia and insulin resistance or hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy. The syndrome has been observed with PIs used in HAART regimens, with an incidence of 30–50% and a median onset time of approximately 1 yr duration of treatment.