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 name
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) Unfortunately, a single-dose pharmacokinetic study revealed
that atazanavir/ritonavir caused a 3-fold increase in the area under the curve
after 24 hours (AUC0-24) and 600% increase in the Cmax of rosuvastatin.(11)
Therefore, the following question remains. How does
atazanavir/ritonavir increase the concentrations of rosuvastatin when there is
no apparent pharmacokinetic interaction based on their product inserts?
Without direct evidence, it would appear that this drug interaction is
being mediated outside of the CYP450 system. There are
data that show rosuvastatin to be a substrate for the efflux pump, breast
cancer resistance protein (BCRP).(12) While BCRP transporters are found on
breast cancer cells, they are also found in many other places including the
apical surfaces of the enterocytes and the bile canalicular membrane of
hepatocytes where they can influence the bioavailability and efflux of drugs
out of the body.(13) In addition, it is now known that atazanavir is an
inhibitor of BCRP.(14) Therefore, it is plausible that atazanavir inhibits
BCRP-mediated enteric and/or biliary efflux of rosuvastatin thereby allowing
for a greater extent of absorption and/or decrease in biliary excretion of
rosuvastatin.(11)
Another
potential mechanism for a reduction in rosuvastatin excretion might be the
inhibition of hepatic uptake of rosuvastatin via the influx transporter organic
anion transporter polypeptide (OATP1B1) in the liver by atazanavir. While
the specific inhibition of OATP1B1 in humans by atazanavir is not known, there
is data in rats that demonstrates that atazanavir is an inhibitor of OATP
(subtypes of OATP not specified).15 This is consistent with the PI,
indinavir which has similar pharmacologic properties to atazanavir.(16) In
addition, a previous drug interaction study between rosuvastatin and
gemfibrozil (a known inhibitor of OAT1B1) showed similar increases in
pharmacokinetic parameters as in the drug interaction study between atazanavir
and rosuvastatin.(17) The last factor involved in atazanavir's ability to
increase rosuvastatin concentrations could be in atazanavir's inhibition of
UGT1A1 in the enterocyte and hepatocyte which is another pathway of metabolism
for rosuvastatin.(9,11)
It
is very apparent that the drug interaction between atazanavir and rosuvastatin
cannot be predicted by only evaluating the approved product labeling and thus
highlights the need for a greater understanding of the various mechanisms for
drug interactions. Due to the 3-fold increase in rosuvastatin
concentrations when coadministered with atazanavir based HAART, the dose of
rosuvastatin should probably be limited to no more than 10 mg a day, similar to
atorvastatin.(11) This is clinically relevant since increased levels
(regardless of the cause) of any statin are known to increase the risk of both
hepatotoxicity and myositis (including rhabdomyolysis).(18-20)
