Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: BRISTOL-MYERS SQUIBB PHARMA EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge UB8 1DH, United Kingdom
Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors
ATC code: J05AE08
Atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.
Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activity in cell culture.
In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of phenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline PI substitutions. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir (with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy.
Table 3. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks):
| Frequency | de novo PI substitution (n=26)a |
|---|---|
| >20% | none |
| 10-20% | none |
a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥400 copies/ml).
The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.
In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients.
Table 4. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks):
| Frequency | de novo PI substitution (n=35)a,b |
|---|---|
| >20% | M36, M46, I54, A71, V82 |
| 10-20% | L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90 |
a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥400 copies/ml).
b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)
None of the de novo substitutions (see Table 4) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population.
The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the major and minor resistance substitutions described previously to be involved in protease inhibitor resistance.
Study 138 is an international randomised, open-label, multicenter, prospective trial of treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir disoproxil fumarate/emtricitabine (300 mg/200 mg tablets once daily). The REYATAZ/ritonavir arm showed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA <50 copies/ml at week 48 (Table 5). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5).
Table 5. Efficacy Outcomes in Study 138a:
| Parameter | REYATAZ/ritonavirb (300 mg/100 mg once daily) n=440 | Lopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 | ||
|---|---|---|---|---|
| Week 48 | Week 96 | Week 48 | Week 96 | |
| HIV RNA <50 copies/ml, % | ||||
| All patientsd | 78 | 74 | 76 | 68 |
| Difference estimate [95% CI]d | Week 48: 1.7% [-3.8%, 7.1%] | |||
| Week 96: 6.1% [0.3%, 12.0%] | ||||
| Per protocol analysise | 86 (n=392f) | 91 (n=352) | 89 (n=372) | 89 (n=331) |
| Difference estimatee [95% CI] | Week 48: -3% [-7.6%, 1.5%] | |||
| Week 96: 2.2% [-2.3%, 6.7%] | ||||
| HIV RNA <50 copies/ml, % by Baseline Characteristicd | ||||
| HIV RNA | ||||
| <100,000 copies/ml | 82 (n=217) | 75 (n=217) | 81 (n=218) | 70 (n=218) |
| ≥100,000 copies/ml | 74 (n=223) | 74 (n=223) | 72 (n=225) | 66 (n=225) |
| CD4 count | ||||
| <50 cells/mm³ | 78 (n=58) | 78 (n=58) | 63 (n=48) | 58 (n=48) |
| 50 to <100 cells/mm³ | 76 (n=45) | 71 (n=45) | 69 (n=29) | 69 (n=29) |
| 100 to <200 cells/mm³ | 75 (n=106) | 71 (n=106) | 78 (n=134) | 70 (n=134) |
| ≥200 cells/mm³ | 80 (n=222) | 76 (n=222) | 80 (n=228) | 69 (n=228) |
| HIV RNA Mean Change from Baseline, log10 copies/ml | ||||
| All patients -3.09 (n=397) | -3.21 (n=360) | -3.13 (n=379) | -3.19 (n=340) | |
| CD4 Mean Change from Baseline, cells/mm³ | ||||
| All patients | 203 (n=370) | 268 (n=336) | 219 (n=363) | 290 (n=317) |
| CD4 Mean Change from Baseline, cells/mm³ by Baseline Characteristic | ||||
| HIV RNA | ||||
| <100,000 copies/ml | 179 (n=183) | 243 (n=163) | 194 (n=183) | 267 (n=152) |
| ≥100,000 copies/ml | 227 (n=187) | 291 (n=173) | 245 (n=180) | 310 (n=165) |
a Mean baseline CD4 cell count was 214 cells/mm³ (range 2 to 810 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml)
b REYATAZ/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).
c Lopinavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).
d Intent-to-treat analysis, with missing values considered as failures.
e Per protocol analysis: Excluding non-completers and patients with major protocol deviations.
f Number of patients evaluable.
In an open-label, randomised, comparative study following a 26- to 30-week induction phase with REYATAZ 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted REYATAZ 400 mg once daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy compared with REYATAZ + ritonavir and two NRTIs (n=85) in HIV infected subjects with fully suppressed HIV replication, as assessed by the proportion of subjects with HIV RNA <50 copies/ml: 78% of subjects on unboosted REYATAZ and two NRTIs compared with 75% on REYATAZ + ritonavir and two NRTIs.
Eleven subjects (13%) in the unboosted REYATAZ group and 6 (7%) in the REYATAZ + ritonavir group, had virologic rebound. Four subjects in the unboosted REYATAZ group and 2 in the REYATAZ + ritonavir group had HIV RNA >500 copies/ml during the maintenance phase. No subject in either group showed emergence of protease inhibitor resistance. The M184V substitution in reverse transcriptase, which confers resistance to lamivudine and emtricitabine, was detected in 2 subjects in the unboosted REYATAZ and 1 subject in the REYATAZ + ritonavir group.
There were fewer treatment discontinuations in the unboosted REYATAZ group (1 vs. 4 subjects in the REYATAZ + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted REYATAZ group compared with the REYATAZ + ritonavir group (18 and 28 subjects, respectively).
Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir disoproxil fumarate (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent of patients in the study had a viral strain with fewer than two NRTI substitutions.
The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 48 weeks (Table 6).
Table 6. Efficacy Outcomes at Week 48a and at Week 96 (Study 045):
| Parameter | ATV/RTVb (300 mg/100 mg once daily) n=120 | LPV/RTVc (400 mg/100 mg twice daily) n=123 | Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] | |||
|---|---|---|---|---|---|---|
| Week 48 | Week 96 | Week 48 | Week 96 | Week 48 | Week 96 | |
| HIV RNA Mean Change from Baseline, log10 copies/ml | ||||||
| All patients | -1.93 (n=90e) | -2.29 (n=64) | -1.87 (n=99) | -2.08 (n=65) | 0.13 [-0.12, 0.39] | 0.14 [-0.13, 0.41] |
| HIV RNA <50 copies/ml, %f (responder/evaluable) | ||||||
| All patients | 36 (43/120) | 32 (38/120) | 42 (52/123) | 35 (41/118) | NA | NA |
| HIV RNA <50 copies/ml by select baseline PI substitutions,f,g % (responder/evaluable) | ||||||
| 0-2 | 44 (28/63) | 41 (26/63) | 56 (32/57) | 48 (26/54) | NA | NA |
| 3 | 18 (2/11) | 9 (1/11) | 38 (6/16) | 33 (5/15) | NA | NA |
| ≥4 | 27 (12/45) | 24 (11/45) | 28 (14/50) | 20 (10/49) | NA | NA |
| CD4 Mean Change from Baseline, cells/mm³ | ||||||
| All patients | 110 (n=83) | 122 (n=60) | 121 (n=94) | 154 (n=60) | NA | NA |
a The mean baseline CD4 cell count was 337 cells/mm³ (range: 14 to 1,543 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml).
b ATV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).
c LPV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).
d Confidence interval.
e Number of patients evaluable.
f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA <400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively.
g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline.
NA = not applicable.
Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained with the last observation carried forward method of analysis (time-averaged difference of 0.11, 97.5% confidence interval [-0.15, 0.36]). By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively.
Through 96 weeks of treatment, mean HIV RNA changes from baseline for REYATAZ + ritonavir and lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96-week analysis, 48% of patients overall remained on study.
REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir.
Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 months to 21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naive and 101 antiretroviral-experienced) received once daily REYATAZ (capsule or powder formulation), with or without ritonavir, in combination with two NRTIs.
The clinical data derived from this study are inadequate to support the use of atazanavir (with or without ritonavir) in children below 6 years of age.
Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received REYATAZ capsules with ritonavir are presented in Table 7. For treatment-naive paediatric patients, the mean baseline CD4 cell count was 344 cells/mm³ (range: 2 to 800 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.67 log10 copies/ml (range: 3.70 to 5.00 log10 copies/ml). For treatment-experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm³ (range: 100 to 1157 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/ml (range: 3.28 to 5.00 log10 copies/ml).
Table 7. Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at Week 48 (Study AI424-020):
| Parameter | Treatment-Naive REYATAZ Capsules/ritonavir (300 mg/100 mg once daily) n=16 | Treatment-Experienced REYATAZ Capsules/ritonavir (300 mg/100 mg once daily) n=25 |
|---|---|---|
| HIV RNA <50 copies/ml, %a | ||
| All patients | 81 (13/16) | 24 (6/25) |
| HIV RNA <400 copies/ml, %a | ||
| All patients | 88 (14/16) | 32 (8/25) |
| CD4 Mean Change from Baseline, cells/mm³ | ||
| All patients | 293 (n=14b) | 229 (n=14b) |
| HIV RNA <50 copies/ml by select baseline PI substitutions,c % (responder/evaluabled) | ||
| 0-2 | NA | 27 (4/15) |
| 3 | NA | - |
| ≥4 | NA | 0 (0/3) |
a Intent-to-treat analysis, with missing values considered as failures.
b Number of patients evaluable.
c PI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY,I54ALMSTV, L76V, V82AFLST, I84V, N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V. d Includes patients with baseline resistance data.
NA = not applicable.
The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients; significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit a non-linear disposition.
In HIV-infected patients (n=33, combined studies), multiple dosing of REYATAZ 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%) ng/ml, with time to Cmax of approximately 2.5 hours. The geometric mean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/ml and 44185 (51%) ng•h/ml, respectively.
In HIV-infected patients (n=13), multiple dosing of REYATAZ 400 mg (without ritonavir) once daily with food produced a geometric mean (CV%) for atazanavir Cmax of 2298 (71) ng/ml, with time to Cmax of approximately 2.0 hours. The geometric mean (CV%) for atazanavir Cmin and AUC were 120 (109) ng/ml and 14874 (91) ng•h/ml, respectively.
Co-administration of REYATAZ and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300 mg dose of REYATAZ and 100 mg dose of ritonavir with a light meal resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24 hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24 hour concentration following a high fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, REYATAZ is to be taken with food.
Atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 ng/ml. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ml). In a multiple-dose study in HIVinfected patients dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.
Studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.
Following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.
In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available for REYATAZ with ritonavir in patients with renal insufficiency. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e. unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.)
Atazanavir is metabolised and eliminated primarily by the liver. REYATAZ (without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400 mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).
A study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29 young, 30 elderly). There were no clinically important pharmacokinetic differences based on age or gender.
A population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.
The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ capsules with ritonavir are presented in Table 8.
Table 8. Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected Pregnant Women in the Fed State:
| atazanavir 300 mg with ritonavir 100 mg | |||
|---|---|---|---|
| Pharmacokinetic Parameter | 2nd Trimester (n=9) | 3rd Trimester (n=20) | postpartuma (n=36) |
| Cmax ng/mL | 3729.09 | 3291.46 | 5649.10 |
| Geometric mean (CV%) | (39) | (48) | (31) |
| AUC ng•h/mL | 34399.1 | 34251.5 | 60532.7 |
| Geometric mean (CV%) | (37) | (43) | (33) |
| Cmin ng/mLb | 663.78 | 668.48 | 1420.64 |
| Geometric mean (CV%) | (36) | (50) | (47) |
a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period (4-12 weeks) than those observed historically in HIV infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2-fold higher during the postpartum period when compared to those observed historically in HIV infected non-pregnant patients.
b Cmin is concentration 24 hours post-dose.
There is a trend toward a higher clearance in younger children when normalised for body weight. As a result, greater peak to trough ratios are observed, however at recommended doses, geometric mean atazanavir exposures (Cmin, Cmax and AUC) in paediatric patients are expected to be similar to those observed in adults.
In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generally confined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic singlecell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at least equal to that observed in humans given 400 mg once daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.
During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μM) of atazanavir corresponding to 30 fold the free drug concentration at Cmax in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2 week oral toxicity study performed in dogs. Subsequent 9 month oral toxicity studies in dogs showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PR prolongation should be considered in cases of overdose (see section 4.9).
In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic doses. In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryodevelopment study. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.
Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.
In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomas in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered to have no relevance for humans at intended therapeutic exposures. There were no tumorigenic findings in male mice or in rats.
Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may be an ocular irritant upon direct contact with the eye.
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