Atazanavir Sulfate (Page 9 of 11)

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 1200 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 atazanavir/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138 was a 96-week, open-label, randomized, multicenter study, comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir DF with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients 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/mm 3 (range: 2 to 810 cells/mm 3) and the mean baseline plasma HIV-1 RNA level was 4.94 log 10 copies/mL (range: 2.60 to 5.88 log 10 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 + ritonavir 100 mg (once daily) with tenofovir DF/emtricitabine (once daily) a (n=441) 96 Weeks lopinavir 400 mg + ritonavir 100 mg (twice daily) with tenofovir DF/emtricitabine (once daily) a (n=437) 96 Weeks
a As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily. b Patients achieved HIV RNA <50 copies/mL at Week 96. Roche Amplicor ® , v1.5 ultra-sensitive assay. c Pre-specified ITT analysis at Week 48 using as-randomized cohort: ATV/RTV 78% and LPV/RTV 76% (difference estimate: 1.7% [95% confidence interval: −3.8%, 7.1%]). d Pre-specified ITT analysis at Week 96 using as-randomized cohort: ATV/RTV 74% and LPV/RTV 68% (difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]). e Includes viral rebound and failure to achieve confirmed HIV RNA <50 copies/mL through Week 96. f Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
Responder b,c,d 75% 68%
Virologic failure e 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 reasons f 4% 7%

Through 96 weeks of therapy, the proportion of responders among patients with high viral loads (i.e., baseline HIV RNA ≥100,000 copies/mL) was comparable for the atazanavir/ritonavir (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm 3 for the atazanavir/ritonavir arm and 273 cells/mm 3 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 was a randomized, double-blind, multicenter trial comparing atazanavir (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients 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/mm 3 (range: 64 to 1424 cells/mm 3) and the mean baseline plasma HIV-1 RNA level was 4.8 log 10 copies/mL (range: 2.2 to 5.9 log 10 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 + lamivudine + zidovudine d (n=405) efavirenz 600 mg once daily + lamivudine + zidovudine d (n=405)
a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor ® HIV-1 Monitor TM Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48. c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons. d As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Responder a 67% (32%) 62% (37%)
Virologic failure b 20% 21%
Rebound 17% 16%
Never suppressed through Week 48 3% 5%
Death - <1%
Discontinued due to adverse event 5% 7%
Discontinued for other reasons c 8% 10%

Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (i.e., baseline HIV 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/mm 3 for the atazanavir arm and 160 cells/mm 3 for the efavirenz arm. Study AI424-008: Atazanavir 400 mg once daily compared to atazanavir 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 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 (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive patients. Patients 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/mm 3 (range: 4 to 1003 cells/m 3) and the mean baseline plasma HIV-1 RNA level was 4.7 log 10 copies/mL (range: 1.8 to 5.9 log 10 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+ lamivudine + stavudine (n=181) nelfinavir 1250 mg twice daily + lamivudine + stavudine (n=91)
a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor ® HIV-1 Monitor TM Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48. c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
Responder a 67% (33%) 59% (38%)
Virologic failure b 24% 27%
Rebound 14% 14%
Never suppressed through Week 48 10% 13%
Death <1% -
Discontinued due to adverse event 1% 3%
Discontinued for other reasons c 7% 10%

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm 3 for the atazanavir 400 mg arm and 211 cells/mm 3 for the nelfinavir arm.

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