ays 17 (N=18 for Cmin) ↓ 0.60
(0.55; 0.67) 0.51
(0.47; 0.55) 0.42
(0.37; 0.47)
Lopinavir (LPV), boosted with ritonavir (rtv) 400 mg LPV/ 100 mg rtv bid for 20 days 750 mg q8h for 10 days 12 ↔
0.96
(0.87; 1.05) 1.06
(0.96; 1.17) 1.14
(0.96; 1.36)
Tenofovir disoproxil fumarate 300 mg qd for 7 days 750 mg q8h for 7 days 16 ↑ 1.30
(1.16; 1.45) 1.30
(1.22; 1.39) 1.41
(1.29; 1.54)
Tenofovir, on co-administration of tenofovir disoproxil fumarate (TDF) and efavirenz (EFV) 600 mg EFV /300 mg TDF qd for 7 days 1125 mg q8h for 7 days 15 ↑
1.22
(1.12; 1.33) 1.10
(1.03; 1.18) 1.17
(1.06; 1.28)
600 mg EFV /300 mg TDF qd for 7 days 1500 mg q12h for 7 days 16 ↑
1.24
(1.13; 1.37) 1.10
(1.03; 1.17) 1.06
(0.98; 1.15)
12.4Microbiology
Mechanism of Action
Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.
Antiviral Activity in Cell Culture
In an HCV subtype 1b replicon assay, the telaprevir EC50 value against wild-type HCV was 354 nM in a 2-day cell culture assay, and in a subtype 1a infectious virus assay, the EC50 value was 280 nM in a 5-day cell culture assay. In biochemical enzymatic assays, the median IC50 values of telaprevir against genotype 2, 3a, and 4a were 16 nM (range 6-32 nM; n=5), 40 nM (range 39-88 nM; n=5), and 130 nM (n=1), respectively, compared to a median IC50 value of 20 nM (range 16-23; n=2) for genotype 1a and 20 nM for genotype 1b (range 13-33; n=4). The presence of 40% human serum reduced the anti-HCV activity of telaprevir by approximately 10-fold. eva luation of telaprevir in combination with interferon alfa or ribavirin showed no evidence of antagonism in reducing HCV-RNA levels in HCV replicon cells.
Resistance
In Cell Culture
HCV genotype 1b replicons with reduced susceptibility to telaprevir have been selected in cell culture and characterized for telaprevir genotypic and phenotypic resistance. Additionally, resistance to telaprevir was eva luated in both biochemical and HCV genotype 1b replicon assays using site-directed mutants and recombinant NS3/4A from telaprevir Phase 2 clinical trials isolates. Variants V36A/M, T54A/S, R155K/T, A156S, R155T+D168N, and V36A+T54A conferred 3- to 25-fold reduced susceptibility to telaprevir; and A156V/T variants and the V36M/A+R155K/T and T54S/A+A156S/T double variants conferred greater than 62-fold reduced susceptibility to telaprevir. No amino acid substitutions were observed at the proteolytic cleavage sites.
In Clinical Studies
In a pooled analysis of subjects who did not achieve SVR (on-treatment virologic failure or relapse) from the controlled Phase 3 clinical trials, NS3 amino acid substitutions V36M/A/L, T54A/S, R155K/T, and A156S/T were determined to emerge frequently on INCIVEK treatment (Table 8). Nearly all of these substitutions have been shown to reduce telaprevir anti-HCV activity in cell culture or biochemical assays. No clear evidence of treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome was observed among INCIVEK-treated subjects who did not achieve SVR.
Telaprevir treatment emergent resistance substitu
