Atazanavir is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; therefore, it should be taken with meals. Separation of ingestion from acid-reducing agents by at least 12 hours is recommended and concurrent proton pump inhibitors are contraindicated. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6–7 hours, which increases to approximately 11 hours when co-administered with ritonavir. The primary route of elimination is biliary; atazanavir should not be given to patients with severe hepatic insufficiency.
Boosted atazanavir is one of the recommended PI agents for use in pregnant women (Table 49–5).
The most common adverse effects in patients receiving atazanavir are diarrhea and nausea; vomiting, abdominal pain, headache, and peripheral neuropathy may also occur. Skin rash, reported in ~20% of patients, is generally mild; however severe rash and Stevens Johnson syndrome have been reported. As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur in approximately 10% of patients, owing to inhibition of the UGT1A1 glucuronidation enzyme. Elevation of serum aminotransferases has separately been observed, usually in patients with underlying HBV or HCV co-infection. Kidney stones, gallstones, PR prolongation, and decreased bone mineral density have also been reported. In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemia or hyperglycemia. The oral powder contains phenylalanine, which can be harmful to patients with phenylketonuria.
As an inhibitor of CYP3A4, CYP2C9, and UGT1A1, the potential for drug-drug interactions with atazanavir is great (Tables 49–3 and 49–4). Due to decreased atazanavir levels, atazanavir should not be administered with bosentan, elvitegravir/ cobicistat, etravirine, fosamprenavir, nevirapine, proton pump inhibitors, or tipranavir. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as irinotecan, may increase its levels. Atovaquone and voriconazole levels may be decreased with coadministration, and levels of maraviroc and ranolazine may be increased.
Darunavir must be co-administered with ritonavir or cobicistat. Darunavir should be taken with meals to improve bioavailability. It is highly protein-bound and primarily metabolized by the liver.
Boosted darunavir is one of the PI agents recommended for use in pregnancy (Table 49–5).
Adverse effects include diarrhea, nausea, headache, and increases in amylase and hepatic aminotransferase levels. Rash occurs in 2–7% of patients and may occasionally be severe. Liver toxicity, including severe hepatitis, has been reported, such that liver function tests should be monitored; the risk may be higher for persons with HBV, HCV, or other chronic liver disease. Darunavir contains a sulfonamide moiety and may cause a hypersensitivity reaction, particularly in patients with sulfa allergy.