52; 0.66) 0.53
(0.45; 0.64) NA
Anti-HIV Drugs
Atazanavir (ATV), boosted with ritonavir (rtv) 300 mg ATV/ 100 mg rtv qd for 20 days 750 mg q8h for 10 days 7 ↔ 0.85
(0.73; 0.98) 1.17
(0.97; 1.43) 1.85
(1.40; 2.44)
Darunavir (DRV), boosted with ritonavir (rtv) 600 mg DRV/ 100 mg rtv bid for 20 days 750 mg q8h for 10 days 11 (N=14 for Cmax) ↓ 0.60
(0.56; 0.64) 0.60
(0.57; 0.63) 0.58
(0.52; 0.64)
600 mg DRV/ 100 mg rtv bid for 24 days 1125 mg q12h for 4 days 15 ↓ 0.53
(0.47; 0.59) 0.49
(0.43; 0.55) 0.42
(0.35; 0.51)
Efavirenz 600 mg qd for 20 days 750 mg q8h for 10 days 21 ↔ 0.84
(0.76; 0.93) 0.93
(0.87; 0.98) 0.98
(0.94; 1.02)
Efavirenz (EFV), co-administered with tenofovir disoproxil fumarate (TDF) 600 mg EFV /300 mg TDF qd for 7 days 1125 mg q8h for 7 days 15 ↓
0.76
(0.68; 0.85) 0.82
(0.74; 0.90) 0.90
(0.81; 1.01)
600 mg EFV /300 mg TDF qd for 7 days 1500 mg q12h for 7 days 16 ↓ 0.80
(0.74; 0.86) 0.85
(0.79; 0.91) 0.89
(0.82; 0.96)
Fosamprenavir (fAPV), boosted with ritonavir (rtv) 700 mg fAPV/ 100 mg bid rtv for 20 days 750 mg q8h for 10 days 18 ↓ 0.65
(0.59; 0.70) 0.53
(0.49; 0.58) 0.44
(0.40; 0.50)
700 mg fAPV/ 100 mg bid rtv for 24 days 1125 mg q12h for 4 days 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)
* The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK
12.4 Microbiology
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 susceptib |
