ps are not meant to represent clinical susceptibility breakpoints for APTIVUS/ritonavir because the data are based on the select 1182.12 and 1182.48 patient population. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to APTIVUS/ritonavir in protease inhibitor-experienced patients.
Table 10 Response by Baseline Tipranavir Phenotype at 48 weeks in the Controlled Clinical Trials 1182.12 and 1182.48
Baseline
Tipranavir
Phenotype
(Fold Change)a |
Proportion of Respondersb with
No New Enfuvirtidec Use
N=211 |
Proportion of Respondersb with
New Enfuvirtided Use
N=68 |
Tipranavir Susceptibility |
|
a Change in tipranavir EC50 value from wild-type reference |
|
b Confirmed ≥1 log10 decrease at Week 48 |
|
c No new enfuvirtide is defined as recycled or continued use of enfuvirtide or no use of enfuvirtide |
|
d New enfuvirtide is defined as initiation of enfuvirtide for the first time |
|
0-3 |
48% (73/153) |
70% (33/47) |
Susceptible |
|
>3-10 |
21% (10/48) |
53% (8/15) |
Decreased Susceptibility |
|
>10 |
10% (1/10) |
50% (3/6) |
Resistant |
Table 11 Correlation of Baseline Tipranavir Phenotype to Genotype using HIV-1 isolates from Phase 2 and Phase 3 Clinical Trials
Baseline
Tipranavir
Phenotype
(Fold Change)a |
# of Baseline Protease Mutations at 33, 82, 84, 90 |
# of Baseline Tipranavir Resistance-Associated Mutationsb |
Tipranavir Susceptibilityc |
a Change in tipranavir EC50 value from wild-type reference
b Number of amino acid substitutions in HIV-1 protease among L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V
c defined by week 48 response |
|
0-3 |
0-2 |
0-4 |
Susceptible |
|
>3-10 |
3 |
5-7 |
Decreased Susceptibility |
|
>10 |
4 |
8+ |
Resistant |
Analyses of pediatric clinical trial 1182.14 also demonstrated that response to therapy was influenced by the number of baseline protease inhibitor mutations present.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies in mice and rats have been conducted with tipranavir. Mice were administered 30, 150 or 300 mg/kg/day tipranavir, 150/40 mg/kg/day tipranavir/ritonavir in combination, or 40 mg/kg/day ritonavir. The incidences of benign hepatocellular adenomas and combined adenomas/carcinomas were increased in females of all groups except the low dose of tipranavir. These tumors were also increased in male mice at the high-dose of tipranavir and the tipranavir/ritonavir combination group. Hepatocellular carcinoma incidence was increased in female mice given the high dose of tipranavir and both sexes receiving tipranavir/
