known as BMS-232632, atazanavir/ATV (Reyataz)
is an azapeptide protease inhibitor (PI) of HIV-1
US Food and Drug Administration (FDA) approved
atazanavir on June 20, 2003 for the treatment
of HIV-1 infection in combination with other antiretroviral
FDA based its approval of atazanavir on data from
two Phase II 48-week trials and from 24 to 48
week data from Phase III studies. Results from
these trials showed a decrease in viral load and
an increase in CD4 cell counts in patients taking
atazanavir in combination with other antiretroviral
became commercially available in the United States
under the principles of the accelerated review
process of the FDA that allow approval based on
analysis of surrogate markers of response (e.g.,
plasma HIV-1 RNA levels), rather than clinical
end points such as disease progression or survival.
There are no results to date from controlled studies
evaluating the effects of atazanavir on clinical
progression of HIV infection.
is a PI with a unique HIV resistance profile that
suggests it may be an appropriate component of
antiviral regimens in treatment-naive patients.
Patients taking atazanavir on their first antiretroviral
regimen develop a characteristic I50L mutation
that increases viral susceptibility to other PIs.
other PIs, atazanavir appears to have a minimal
effect on lipid levels.
use of atazanavir may be considered in antiretroviral-experienced
adults with HIV strains that are expected to be
susceptible to atazanavir by genotypic and phenotypic
Atazanavir is an azapeptide PI that selectively inhibits the
virus-specific processing of viral Gag and Gag-Pol
polyproteins in HIV-1 infected cells. Atazanavir
exhibits anti-HIV-1 activity with a mean 50% effective
concentration (EC50) in the absence of human serum
of 2 to 5 nM against a variety of laboratory and
clinical HIV-1 isolates grown in peripheral blood
mononuclear cells, macrophages, CEM-SS cells,
and MT-2 cells.
combination studies with atazanavir showed additive
to antagonistic antiviral activity in vitro with
the NRTI abacavir (Ziagen) and the non
nucleoside reverse transcriptase inhibitors
(Rescriptor), efavirenz (Sustiva),
and nevirapine (Viramune)
and additive antiviral activity in vitro with
the PIs amprenavir
(Kaletra), ritonavir (Norvir), and
Atazanavir is rapidly
absorbed, with a median time to maximum plasma
concentration of approximately 2.5 hours in healthy
people and 2 hours in HIV infected patients. Steady-state
is achieved between days 4 and 8, with an accumulation
of approximately 2.3-fold. The pharmacokinetics
of atazanavir in pediatric patients are under
investigation. Administration of atazanavir with
a light meal resulted in a 70% increase in AUC
and a 57% increase in Cmax relative to the fasting state. Administration of a single 400
mg dose of atazanavir with a high-fat meal resulted
in a mean increase in AUC of 35% and no change
in Cmax relative to the fasting state.
In a multiple-dose
study in HIV-infected patients taking 400 mg atazanavir
once daily with a light meal for 12 weeks, atazanavir
was detected in the cerebrospinal fluid (CSF)
Atazanavir is in FDA Pregnancy Category B. There have been
no adequate and well-controlled studies of atazanavir
in pregnant women. Atazanavir should be used in
pregnancy only if the potential benefit to the
mother justifies the potential risk to the fetus.
No significant effects on mating, fertility, or
early embryonic development were observed in rats
given daily doses up to two times the human clinical
dose of 400 mg once daily.
In studies with rabbits and rats given doses producing drug
exposure levels up to two times the human clinical
dose, atazanavir did not produce teratogenic effects.
However, in pre- and postnatal studies of rats
given atazanavir at maternally toxic exposure
levels, two times the human clinical dose caused
weight loss or weight gain suppression in the
offspring. An Antiretroviral Pregnancy Registry
has been established to monitor the outcomes of
pregnant women exposed to antiretroviral agents.
Physicians may register their patients by calling
1-800-258-4263 or at http://www.APRegistry.com
It is not known
whether atazanavir is secreted in human breast
milk; however, it is distributed into the milk
of rats. Because of both the potential for HIV
transmission and the potential for serious adverse
reactions in the nursing infant, mothers should
be instructed not to breast-feed if they are receiving
Atazanavir is extensively
metabolized in the liver by CYP3A and inhibits
CYP3A and UGT1A1. The major biotransformation
pathways of atazanavir consist of monooxygenation
and dioxygenation. Elimination half-life of healthy
or HIV infected adults is approximately 7 hours
following a 400 mg daily dose with a light meal.
Atazanavir is primarily eliminated in the feces
(79%) and the urine (13%). Unchanged drug accounted
for approximately 20% and 7% of the administered
dose in the feces and urine, respectively.
Atazanavir is highly
selective for HIV-1 protease and exhibits cytotoxicity
at concentrations 6,500- to 23,000-fold higher
than concentrations required for therapeutic antiviral
activity. This selectivity index is comparable
to or better than that of other PIs.
Data to date indicate that atazanavir has a resistance profile
distinct from that of other PIs. Treatment-naive
patients developed a characteristic I50L mutation
and increased susceptibility to other PIs. In
contrast, treatment-experienced patients did not
develop the I50L mutation; rather, these patients
developed mutations (I84V, L90M, A71V/T, N88S/D,
and M46I) that reduced response to atazanavir
and conferred high cross resistance to other protease.
Events / Toxicities and Side Effects
Adverse effects observed with clinical use of atazanavir include
allergic reaction; new onset or exacerbation of
existing diabetes mellitus or hyperglycemia; asymptomatic
hyperbilirubinemia, including yellow eyes or skin;
lactic acidosis; PR interval prolongation; abdominal
pain; back pain; increased cough; depression;
diarrhea; headache; jaundice; lipodystrophy; nausea;
scleral icterus; or vomiting. Incidences of these
adverse effects cannot be determined because of
insufficient data. However, headache, nausea,
and skin rash were reported in clinical trials
as the most common treatment-emergent adverse
effects of moderate or severe intensity.
Cases of lactic
acidosis syndrome (LAS), sometimes
fatal, and symptomatic hyperlactatemia
have been reported in patients receiving
atazanavir in combination with nucleoside analogues.
Nucleoside analogues, female gender, and obesity
are all known risk factors for LAS. The contribution
of atazanavir to the development of LAS has not
In contrast to
other PIs, neither cholesterol nor triglycerides
increased significantly in patients whose study
regimen contained atazanavir. These characteristics
of atazanavir have made the drug an attractive option in PI-based HAART.
Atazanavir should be administered with food.
Coadministration of Atazanavir with Other Anti-HIV
of atazanavir with efavirenz
(Sustiva) decreases atazanavir AUC and
minimum concentration (Cmin) approximately 70%.
This decreased exposure is due to the CYP3A4 induction
effects of efavirenz. Similar effects would presumably
occur when atazanavir is administered concomitantly
/ Ritonavir / Efavirenz
is recommended that atazanavir be administered
(Norvir) when atazanavir is to
be coadministered with efavirenz as part of an
HIV treatment regimen.
In an attempt to overcome the effects of CYP3A4 induction
when coadministered with efavirenz, atazanavir
has been paired with various doses of ritonavir.
When ritonavir (100 mg once daily) was added
to a 300 mg once daily dose of atazanavir, atazanavir
Cmin was increased approximately 10-fold above
that observed in the absence of ritonavir, while
the AUC and Cmax were increased 3.3- and 1.8-fold,
respectively. This ritonavir-augmented exposure
appears likely to permit atazanavir and efavirenz
Atazanavir / Tenofovir
(Viread) may decrease the AUC and Cmin of atazanavir if the two medications are
taken concurrently. Atazanavir AUC and Cmin were
decreased by approximately 25% and 40%, respectively,
when unboosted atazanavir was coadministered with
/ Tenofovir / Ritonavir
When atazanavir boosted with ritonavir was coadministered with
tenofovir, atazanavir AUC and Cmin were decreased
by approximately 25% and 23%, respectively, as
compared to boosted atazanavir without tenofovir.
coadministered with tenofovir, it is recommended
that 300 mg atazanavir be given with 100 mg ritonavir
and 300 mg tenofovir, all as a single dose with
should not be coadministered with tenofovir unless
it is administered along with ritonavir. Atazanavir increases tenofovir
concentrations by approximately 24%; the increase
in tenofovir AUC did not appear to be associated
with increased toxicity during a 24-week study.
There were no clinically
significant effects on the AUC of zidovudine
(Retrovir), lamivudine (Epivir),
or stavudine (Zerit) when
administered concomitantly with atazanavir, and
no dosage adjustment was necessary.
Atazanavir / Didanosine
A pharmacokinetic study of nucleoside analogue interactions
in healthy individuals showed that coadministration
of atazanavir and didanosine
(ddI; Videx) reduces atazanavir exposure
by fourfold as assessed by AUC. However, this
reduction was believed to be mediated by the antacid
in the buffered formulation of didanosine and
was avoided by administering atazanavir one hour
after buffered didanosine. This interaction
is not expected to occur with the enteric-coated
formulation of didanosine, which does not include
an antacid buffering agent.
Atazanavir / Saquinavir
of atazanavir and saquinavir
with a high-fat meal resulted in a fourfold to
sevenfold increase in saquinavir AUC.
Coadministration of Atazanavir with Other Frequently-used
of atazanavir and rifabutin (Rifampin)
resulted in a twofold increase in rifabutin AUC;
a dosage reduction of rifabutin is recommended.
Atazanavir / Diltiazem
of atazanavir and diltiazem resulted in a twofold increase in
diltiazem AUC; a dosage reduction of diltiazem
is recommended, along with electrocardiogram
Atazanavir / Clarithromycin
of atazanavir and clarithromycin resulted in a
1.9-fold increase in clarithromycin AUC and a
30% increase in atazanavir AUC.
Increased concentrations of clarithromycin may
cause QTc prolongations. When atazanavir is concurrently
administered with clarithromycin, concentrations
of the active metabolite 14-OH clarithyromycin
are significantly reduced while concentrations
of atazanavir are increased. Dose reduction
of clarithromycin should be considered. Alternative
therapy for indications other than Mycobacterium
avium infections should be considered.
Atazanavir / Amiodarone, Lidocaine, or Quinidine
Concurrent administration of atazanavir with amiodarone, lidocaine,
or quinidine may increase antiarrhythmic drug
concentrations, resulting in potentially serious
or life-threatening adverse events. Caution
and concentration monitoring is suggested.
CYP34A or Statin Drugs
Numerous drug interaction studies have been undertaken as part
of the clinical development plan for atazanavir.
Further studies of interactions with nevirapine,
oral contraceptives, and methadone have not yet
been completed. The most substantial effects
are observed with coadministered drugs that are
substrates or inhibitors of CYP3A4. Further
studies are needed of atazanavir coadministered
with statin drugs.
with Omeprazole (proton-pump inhibitor) or H2 Antagonists
In a drug interaction study of atazanavir 300 mg and ritonavir
100 mg coadministered with the proton-pump inhibitor
omeprazole 40 mg, a 76% reduction in atazanavir
AUC and a 78% reduction in atazanavir Cmin were
observed. Coadministration of these agents
is not recommended by the manufacturer. Because
no data are available on the omeprazole 20 mg
formulation, the manufacturer advises against
its coadministration as well. Reduced plasma concentrations
are expected if H2-antagonists are coadministered
with atazanavir, so these drugs are preferably
given 12 hours apart.
Atazanavir and Erectile Dysfunction Drugs or PDE5
Caution should be used when prescribing PDE5 inhibitors for
erectile dysfunction (e.g., sildenafil, tadalafil,
or vardenafil) to patients receiving PIs, including
atazanavir. Coadministration of a PI with a PDE5
inhibitor is expected to substantially increase
the adverse events associated with PDE5 inhibitors,
including hypotension, visual changes, and priapism.
Atazanavir is contraindicated in patients with known hypersensitivity
to atazanavir or any of its ingredients. Coadministration
of atazanavir is contraindicated with drugs that
are highly dependent on CYP3A for clearance,
including benzodiazepines (midazolam, triazolam);
ergot derivatives (dihydroergotamine, ergotamine,
ergonovine, methylergonovine); gastrointestinal
(GI) motility agents (cisapride); and neuroleptics
of atazanavir is also contraindicated with rifampin,
irinotecan, bepridil, lovastatin, simvastatin,
indinavir, proton-pump inhibitors including omeprazole,
and St. John's wort.
has been shown to prolong the PR interval of the
electrocardiogram, risk-benefit should be considered
in patients with pre-existing atrioventricular
(AV) conduction abnormalities. Risk-benefit should
also be considered in patients with obesity, diabetes
mellitus, or hyperglycemia; hepatic function impairment,
elevated transaminase levels, or hepatitis B or
C infection; or type A or B hemophilia (atazanavir
may induce increased bleeding, spontaneous skin
hematomas, and hemarthrosis).
www.ClinicalTrials.gov or www.Acria.org
for trials that use atazanavir.
Atazanavir is dosed orally in capsule form.
Dosage Form: Capsules containing
100, 150, or 200 mg of atazanavir. For antiretroviral
naive patients, the recommended dose of atazanavir
is 400 mg (two 200-mg capsules) once daily.
The recommended dose of atazanavir in antiretroviral-experienced
patients is 300 mg (two 150-mg capsules) taken
with ritonavir 100 mg once daily with food.
of Atazanavir / Efavirenz AND Atazanavir / Tenofovir
When coadministered with efavirenz, it is recommended
that atazanavir 300 mg and ritonavir 100 mg be
given with efavirenz 600 mg (all as a single
daily dose). When coadministered with tenofovir,
it is recommended that atazanavir 300 mg be given
with ritonavir 100 mg and tenofovir
300 mg, all in a single daily dose with food.
Dosing modification may be appropriate for coadministration
of atazanavir and other antiretroviral agents;
recommendations for dosing modification are included
in the Reyataz
A more current version may be available on the Bristol-Myers
Squibb web site. www.bms.com
A dose reduction to 300 mg once daily should be considered
for patients with moderate hepatic insufficiency
(Child-Pugh Class B).
Storage: Store at 25 C (77 F); excursions
permitted to 15 C to 30 C (59 F to 86 F).