Volume 1, Issue 15, 04/28/2009
How does the protease inhibitor, atazanavir (Reyataz®) that is used in the treatment of human immunodeficiency virus (HIV) significantly increase the levels of the statin, rosuvastatin (Crestor®) if they have different CYP450 profiles?
The treatment of human immunodeficiency virus (HIV) infection with highly active antiretroviral therapy (HAART) has dramatically reduced morbidity and mortality related to acquired immunodeficiency syndrome (AIDS).(1,2) However, these improvements have come with some cost as cardiovascular (CV) complications related to antiretroviral therapy that warrant additional treatment have been revealed.(3,4) It is now well recognized that antiretrovirals not only cause insulin resistance and dyslipidemia, but also contribute to an increased risk for cardiovascular disease (CVD) in HIV patients.(1,3,4) Unfortunately, management of antiretroviral-associated metabolic complications will remain a challenge even for the experienced clinician.(5) This is in part due to the extensive profile of drug interactions associated with HAART. More specifically, the use of certain potent lipid lowering agents is limited by these interactions thereby making it more difficult to achieve patient specific lipid goals as recommended by national guidelines.(1)
One of the first line protease inhibitors (PI) used in clinical practice and recommended by national guidelines is atazanavir (Reyataz®) (typically given in combination with ritonavir to enhance the efficacy of atazanavir).(6) Atazanavir not only works well to control the HIV, but it also causes less glucose abnormalities and dyslipidemia as compared to other protease inhibitors.(7,8) As such, atazanavir may be used more often in patients with known CV risk factors or existing CVD when a PI is required. As it relates to potential drug interactions, the product package insert indicates that atazanavir is a metabolism dependent inhibitor of cytochrome P450 (CYP) CYP3A4 and a direct inhibitor of CYP2C8 and UDP-glycosyltransferase (UGT)1A1.(9) This becomes relevant when deciding which lipid lowering agent to initiate when the patient requires treatment or CV risk reduction. Due to the greater dependency of atorvastatin, lovastatin, and simvastatin on CYP3A4 for their metabolism, their use is either dose limited (as with atorvastatin) or contraindicated (as with lovastatin and simvastatin).(1,6) This can be a problem if significant low density lipoprotein (LDL) reductions are needed. As such, rosuvastatin (Crestor®) is the only remaining high potency statin available whose pharmacokinetic profile would not appear to interact with atazanavir coadministration. The product package insert indicates that rosuvastatin undergoes metabolism by CYP2C9 (10%) with the majority of its excretion being in the feces (90%).(10) If a clinician were to compare the product package inserts for both atazanavir and rosuvastatin, it would be plausible for them to conclude that no drug-drug interaction is likely to occur.(9,10)
There is an figure that outlines the specific mechanism for this drug interaction available with this issue.
Other keywords found in this issue: hepatotoxicity, rhabdomyolysis, enterocyte, bile canalicular, hepatocyte, influx, efflux, transporters, BCRP, OATP, UGT1A1
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