Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir.
The efficacy of HIV-1 protease inhibitors (PIs) as part of highly active antiretroviral therapy is now well established and has provided benefits to many patients with HIV infection. Atazanavir is a new azapeptide PI compound that was recently approved in the US and Europe. Atazanavir is recommended in combination with other antiretroviral agents for the treatment of HIV-1 infection. Atazanavir is rapidly absorbed and administration of a single dose of atazanavir with a light meal resulted in a 70% increase in area under the plasma concentration-time curve (AUC); therefore atazanavir should be taken with food. Atazanavir is 86% bound to human serum protein independently of concentration. Concentration in body fluids appeared to be lower than plasma concentration. Like other PIs, atazanavir is extensively metabolised by hepatic cytochrome P450 ( CYP) 3A isoenzymes. The mean terminal elimination half-life in healthy volunteers was approximately 7 hours at steady state following administration of atazanavir 400 mg daily with a light meal. When atazanavir 300 mg was coadministered with ritonavir 100 mg on a once-daily dosage regimen, atazanavir AUC from 0 to 24 hours and minimum plasma concentration were increased by 3- to 4-fold and approximately 10-fold, respectively, compared with atazanavir 300 mg alone. Therefore, ritonavir boosted atazanavir regimen (ritonavir 100 mg and atazanavir 300 mg once daily) is increasingly favoured in some patients. Efavirenz, a potent CYP3A inducer, decreased atazanavir concentrations by 75% and, unexpectedly, tenofovir, a nucleotide reverse transcriptase inhibitor, decreased atazanavir concentrations by 25%.Average predose concentrations in HIV-infected patients who received atazanavir 400mg once daily were 273 ng/mL, which was believed to be several-fold higher than protein-binding corrected 50% inhibitory concentration of wild-type viruses. In HIV-infected patients who received once-daily ritonavir (100mg) boosted atazanavir (300 mg), mean (+/-SD) trough concentration was 862 (+/-838) ng/mL. Several clinical trials showed the efficacy of atazanavir 400 mg once daily with a nucleoside analogue backbone in antiretroviral-naive patients. The atazanavir 300/ritonavir 100 mg once-daily combination coadministered with other antiretrovirals showed the efficacy of this strategy in patients receiving efavirenz or in moderately antiretroviral-experienced HIV-infected patients. Recommended once-daily doses of atazanavir taken with food are either 400 mg or 300 mg in combination with low dose ritonavir (100 mg) in moderately antiretroviral-experienced patients. Major advantages of atazanavir to date are its simplicity of administration (once-daily administration) and its less undesirable effect on the lipid profiles in patients.[1]References
- Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Le Tiec, C., Barrail, A., Goujard, C., Taburet, A.M. Clinical pharmacokinetics. (2005) [Pubmed]
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