e susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
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6 Increase = ↑; Decrease = ↓; No Effect = ↔ 7 Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for efavirenz alone. 8 95% CI 9 Soft Gelatin Capsule 10 90% CI not available 11 Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). 12 Increase = ↑; Decrease = ↓; No Effect = ↔ 13 Compared with atazanavir 400 mg qd alone. 14 Comparator dose of indinavir was 800 mg q8h × 10 days. 15 Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for lopinavir/ritonavir alone. 16 Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent efavirenz. 17 95% CI 18 Soft Gelatin Capsule. 19 Not available because of insufficient data. 20 90% CI not available 21 Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). 22 All interaction trials conducted in healthy volunteers. 23 Subjects received tenofovir DF 300 mg once daily. 24 Increase = ↑; Decrease = ↓; No Effect = ↔ 25 Reyataz Prescribing Information 26 All interaction trials conducted in healthy volunteers. 27 Subjects received tenofovir DF 300 mg once daily. 28 Increase = ↑; Decrease = ↓; No Effect = ↔ 29 Reyataz Prescribing Information 30 In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and C 31 All interaction trials conducted in healthy volunteers. 32 Subjects received tenofovir DF 300 mg once daily. 33 Administration with food was with a light meal (~373 kcal, 20% fat). 34 Increase = ↑; Decrease = ↓; No Effect = ↔ 35 Includes 4 subjects weighing <60 kg receiving ddI 250 mg. Close
NONCLINICAL TOXICOLOGY
Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known.
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