Atazanavir with other protease inhibitors

Other protease inhibitors have also been rarely associated with kidney injury. A single case of interstitial nephritis and reversible AKI in a patient treated with atazanavir has also been reported [153] Acute kidney injury attributed to ritonavir has been reported in several patients [154-157], the majority of whom were receiving concomitant nephrotoxic medications, while others had preexisting kidney disease or were volume depleted. In several patients, AKI recurred upon ritonavir rechallenge. Kidney biopsies were not performed, so histopathologic correlates and etiology of kidney injury were not precisely defined. 

Atazanavir is a protease inhibitor, that inhibits HIV protease, the enzyme required to form functional proteins in HIV-infected cells. Atazanavir, in combination with other antiviral agents, is indicated for the treatment of... 

Although information is limited, these pharmacokinetic interactions are predictable, and potentially serious. To date, clinically relevant increases in calcium-channel blocker levels or effects have been shown for nelfinavir with nifedipine or felodipine, indinavir/ritonavir with amlodipine, diltiazem or nifedipine, and atazanavir with diltiazem. Caution would be required with any of these combinations, anticipating the need to use lower doses of the calcium-channel blocker. The manufacturers specifically recommend that if diltiazem is given with atazanavir the initial dose of diltiazem should be reduced by 50% with subsequent dose titration and ECG monitoring. They also note that verapamil levels may be raised and therefore advise caution. Similarly, the manufaeturers of nifedipine say that blood pressure monitoring is required and a reduction in nifedipine dose may be neeessary if it is given with HIV-protease inhibitors. However, some UK manufacturers (e.g. felodipine, lercanidipine, nimodipine ) recommend avoiding the concurrent use of ritonavir and other protease inhibitors if possible. 

Atazanavir is an azapeptide protease inhibitor. It is active against HIV-1. Following the binding of atazanavir to the HIV protease, the protease is no longer able to process the gag-pol polyprotein precursors. This results in the production of immature HIV particles that lack the capability to infect other cells. The resistance to the drug results from site-directed mutagenesis of viral protease. The resistance is associated with codon 50. In combination with other antiretroviral agents, atazanavir is indicated for the treatment of HIV infection. 

Atazanavir Atazanavir is a peptide protease inhibitor that is active against both HlV-1 and HlV-2. Absorption is increased by food and it is recommended that the drug be administered with a meal. Absorption may be pH dependent, because proton pump inhibitors substantially reduce drug concentration after oral dosing. Like indinavir, atazanavir frequently causes unconjugated hyperbilirubinemia. The drug may be less likely than other HIV protease inhibitors to cause lipodystrophy. 

Atazanavir is an antiretroviral agent approved for use in combination with other antiretroviral agents for the treatment of HIV infections. Atazanavir is a peptidomimetic transition-state inhibitor that targets HIV-1 protease and reduces the viral replication and, thus, the virulence of HIV-1. Similar to saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir, the drug is used in combination with RT inhibitors to produce excellent efficacy in patients with AIDS. 

Buffered didanosine decreases the AUC of indinavir, and the drugs shouid be given one hour apart. Buffered didanosine interacts simiiarly with atazanavir. Tipranavir with low-dose ritonavir modestly reduced the AUC of abacavir and zidovudine, and such combinations are not recommended in the UK. The changes in pharmacokinetics seen when giving other combinations of protease inhibitors with NRTIs do not appear to be clinically significant. Protease inhibitors do not affect the intracellular activation of NRTIs. 

Various dual combinations of proteas e inhibitors have been tried, or are us ed, to boos t the levels and cons equently the efficacy of one of the proteas e inhibitors . Ritonavir is the mos t potent at boos ting levels of the other proteas e inhibitors , and current guidelines recommend the us e of low-dos e ritonavir in combination with atazanavir, darunavir, fos amprenavir, lopinavir, s aquina-vir, or tipranavir. Some proteas e inhibitor combinations may re-s ult in additive toxicity (indinavir and ritonavir or atazanavir). Although this monograph s ummaris es the pharmacokinetic interactions and dos ing recommendations current guidelines should be consulted when choosing protease inhibitor combinations. 

Metabolism In a systematic review of nine randomized controlled studies of atazanavir or atazanavir-I-ritonavir in 3346 patients, there were changes in plasma lipid concentrations, which were lower after 48 weeks of therapy with atazanavir-I-ritonavir than with other ritonavir-boosted protease inhibitor regimens [104 ]. Total and non-HDL cholesterol were higher with atazanavir-I-ritonavir than with atazanavir alone. 

Atazanavir 21 is an acyclic aza-peptidomimetic and potent human immimodeficiency virus (HfV) protease inhibitor [44, 45]. (S)-Tertiary leucine 22 (Figure 4.8) is a key intermediate required for the synthesis of atazanavir along with other drugs containing peptides such as boceprevir and telaprevir [46,47]. 

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