REYATAZ® (atazanavir sulfate) is an azapeptide inhibitor of HIV-1 protease.
The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:
Atazanavir sulfate is a white to pale yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C.
REYATAZ Capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue #2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.
CLINICAL PHARMACOLOGY
Microbiology
Mechanism of Action
Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
Antiviral Activity In Vitro
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. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9 to 32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination studies with ATV showed additive to antagonistic antiviral activity in vitro with abacavir and the NNRTIs (delavirdine, efavirenz, and nevirapine) and additive antiviral activity in vitro with the PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.
Resistance
In vitro: HIV-1 isolates with a decreased susceptibility to ATV have been selected in vitro and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates that were 93- to 183-fold resistant to ATV from three different viral strains were selected in vitro by 5 months. The mutations in these HIV-1 viruses that contributed to ATV resistance included I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L mutation were growth impaired and displayed increased in vitro susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.
Clinical Studies of Treatment-Naive Patients: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure developed an I50L mutation (after an average of 50 weeks of ATV therapy), often in combination with an A71V mutation. In treatment-naive patients, viral isolates that developed the I50L mutation showed phenotypic resistance to ATV but retained in vitro susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L mutation on the efficacy of subsequently administered PIs.
Clinical Studies of Treatment-Experienced Patients: In contrast, from studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed mutations that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease mutations to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other mutations that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance mutations were present in the HIV-1 of the patient at baseline, ATV resistance developed through mutations associated with resistance to other PIs and could include the development of the I50L mutation. The I50L mutation has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.
Cross-Resistance
Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced subjects showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with mutations that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N mutation in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L mutation in addition to other PI resistance-associated mutations were also cross-resistant to other PIs.
Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic response at 48 weeks and the number and type of primary PI-resistance-associated mutations detected in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV twice daily in Study AI424-045 is shown in Table 1.
Overall, both the number and type of baseline PI mutations affected response rates in treatment-experienced patients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI mutations including a mutation at position 36, 71, 77, 82, or 90 were present compared to patients with 1-2 PI mutations including one of these mutations.
Table 1: HIV RNA Response by Number and Type of Baseline PI Mutation, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis
Virologic Response = HIV RNA <400 copies/mLb
Number and Type of Baseline PI Mutationsa
ATV/RTV
(n=110)
LPV/RTV
(n=113)
a Primary mutations include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.
b Results should be interpreted with caution because the subgroups were small.
c There were insufficient data (n<3) for PI mutations V32I, I47V, G48V, I50V, and F53L.
3 or more primary PI mutations including:c
D30N
75% (6/8)
50% (3/6)
M36I/V
19% (3/16)
33% (6/18)
M46I/L/T
24% (4/17)
23% (5/22)
I54V/L/T/M/A
31% (5/16)
31% (5/16)
A71V/T/I/G
34% (10/29)
39% (12/31)
G73S/A/C/T
14% (1/7)
38% (3/8)
V77I
47% (7/15)
44% (7/16)
V82A/F/T/S/I
29% (6/21)
27% (7/26)
I84V/A
11% (1/9)
33% (2/6)
N88D
63% (5/8)
67% (4/6)
L90M
10% (2/21)
44% (11/25)
Number of baseline primary PI mutationsa
All patients, as-treated
58% (64/110)
59% (67/113)
0-2 PI mutations
75% (50/67)
75% (50/67)
3-4 PI mutations
41% (14/34)
43% (12/28)
5 or more PI mutations
0% (0/9)
28% (5/18)
The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by baseline phenotype (shift in in vitro susceptibility relative to reference, Table 2). The analyses are based on a select patient population with 62% of patients receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.
Table 2: Baseline Phenotype by Outcome, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis
Virologic Response = HIV RNA <400 copies/mLb
Baseline Phenotypea
ATV/RTV
(n=111)
LPV/RTV
(n=111)
a Fold change in in vitro susceptibility relative to the wild-type reference.
b Results should be interpreted with caution because the subgroups were small.
0-2
71% (55/78)
70% (56/80)
>2-5
53% (8/15)
44% (4/9)
>5-10
13% (1/8)
33% (3/9)
>10
10% (1/10)
23% (3/13)
Pharmacokinetics
The pharmacokinetics of atazanavir were eva luated in healthy adult volunteers and in HIV-infected patients after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 3).
Table 3: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or HIV-Infected Patients in the Fed State
