Atazanavir (Page 9 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1,200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.

Mutagenesis

Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).

Impairment of Fertility

At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.

14 CLINICAL STUDIES

14.1 Adult Patients without Prior Antiretroviral Therapy

Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of either atazanavir or lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in treatment-naive subjects with HIV-1infection. Study AI424-138 (NCT00272779) was a 96-week, open-label, randomized, multicenter study, comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with the fixed-dose product, tenofovir DF/emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive subjects. Subjects had a mean age of 36 years (range: 19 to 72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26.

Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138)

Outcome

Atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine

(once daily)a

(n=441)

96 Weeks

Lopinavir/ritonavirb

400 mg/100 mg

(twice daily) with tenofovir DF/emtricitabine

(once daily)a

(n=437)

96 Weeks

Responderc,d,e

75%

68%

Virologic failuref

17%

19%

Rebound

8%

10%

Never suppressed through Week 96

9%

9%

Death

1%

1%

Discontinued due to adverse event

3%

5%

Discontinued for other reasonsg

4%

7%

a As a fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily.

b As a fixed-dose product: 400 mg lopinavir/100 mg ritonavir (twice daily).

c Subjects achieved HIV-1 RNA < 50 copies/mL at Week 96. Roche Amplicor® , v1.5 ultra-sensitive assay.

d Pre-specified ITT analysis at Week 48 using as-randomized cohort: atazanavir with ritonavir 78% and lopinavir/ritonavir 76% (difference estimate: 1.7% [95% confidence interval: −3.8%, 7.1%]).

e Pre-specified ITT analysis at Week 96 using as-randomized cohort: atazanavir with ritonavir 74% and lopinavir/ritonavir 68% (difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]).

f Includes viral rebound and failure to achieve confirmed HIV-1 RNA < 50 copies/mL through Week 96.

g Includes lost to follow-up, subject’s withdrawal, noncompliance, protocol violation, and other reasons.

Through 96 weeks of therapy, the proportion of responders among subjects with high viral loads (i.e. baseline HIV-1 RNA ≥ 100,000 copies/mL) was comparable for the atazanavir with ritonavir (165 of 223 subjects, 74%) and lopinavir/ritonavir (148 of 222 subjects, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the atazanavir with ritonavir arm and 273 cells/mm3 for the lopinavir/ritonavir arm.

Study AI424-034: Atazanavir once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. Study AI424-034 (NCT00013897) was a randomized, double-blind, multicenter trial comparing atazanavir (400 mg once daily) to efavirenz (600 mg once daily), each in combination with the fixed-dose product of lamivudine /zidovudine (150 mg/300 mg) given twice daily, in 810 antiretroviral treatment-naive subjects. Subjects had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1,424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range:

2.2 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27.

Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034)

Outcome

Atazanavir

400 mg once daily and lamivudine/zidovudined

(n=405)

Efavirenz

600 mg once daily and lamivudine/zidovudined

(n=405)

Respondera

67% (32%)

62% (37%)

Virologic failureb

20%

21%

Rebound

17%

16%

Never suppressed through Week 48

3%

5%

Death

< 1%

Discontinued due to adverse event

5%

7%

Discontinued for other reasonsc

8%

10%

a Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL (< 50 copies/mL) through Week 48. Roche Amplicor® HIV-1 MonitorTM Assay, test version 1.0 or 1.5 as geographically appropriate.

b Includes viral rebound and failure to achieve confirmed HIV-1 RNA < 400 copies/mL through Week 48.

c Includes lost to follow-up, subject’s withdrawal, noncompliance, protocol violation, and other reasons.

d As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily.

Through 48 weeks of therapy, the proportion of responders among subjects with high viral loads (i.e. baseline HIV-1 RNA ≥ 100,000 copies/mL) was comparable for the atazanavir and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the atazanavir arm and 160 cells/mm3 for the efavirenz arm.

Study AI424-008: Atazanavir 400 mg once daily compared to atazanavir 600 mg once daily, and compared to nelfinavir 1,250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 (NCT identifier not available) was a 48-week, randomized, multicenter trial, blinded to dose of atazanavir, comparing atazanavir at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1,250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive subjects. Subjects had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male.

The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1,003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28.

Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008)

Outcome

Atazanavir 400 mg once daily with lamivudine and stavudine (n=181)

Nelfinavir 1,250 mg twice daily with lamivudine and stavudine (n=91)

Respondera

67% (33%)

59% (38%)

Virologic failureb

24%

27%

Rebound

14%

14%

Never suppressed through Week 48

10%

13%

Death

< 1%

Discontinued due to adverse event

1%

3%

Discontinued for other reasonsc

7%

10%

a Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL (< 50 copies/mL) through Week 48. Roche Amplicor® HIV-1 Monitor Assay, test version 1.0 or 1.5 as geographically appropriate.

b Includes viral rebound and failure to achieve confirmed HIV-1 RNA < 400 copies/mL through Week 48.

c Includes lost to follow-up, subject’s withdrawal, noncompliance, protocol violation, and other reasons.

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the atazanavir 400-mg arm and 211 cells/mm3 for the nelfinavir arm.

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