ialysis.
11 DESCRIPTION
INCIVEK (telaprevir) is an inhibitor of the HCV NS3/4A protease.
The IUPAC name for telaprevir is (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide. Its molecular formula is C36H53N7O6 and its molecular weight is 679.85. Telaprevir has the following structural formula:
Telaprevir drug substance is a white to off-white powder with a solubility in water of 0.0047 mg/mL.
Telaprevir interconverts to an R-diastereomer, VRT-127394, which is the major metabolite in plasma and is approximately 30-fold less potent than telaprevir.
INCIVEK is available as a purple, capsule-shaped, film-coated tablet for oral administration containing 375 mg of telaprevir. Each tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, D&C Red No. 40, dibasic calcium phosphate (anhydrous), FD&C Blue No. 2, hypromellose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium stearyl fumarate, talc, and titanium dioxide.
Chemical Structure 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Telaprevir is a direct-acting antiviral agent (DAA) against the hepatitis C virus [see Microbiology (12.4) ].
12.2 Pharmacodynamics
ECG eva luation
The effect of telaprevir 750 and 1875 mg on QTc interval was eva luated in a double-blind, double-dummy, randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT study in 44 subjects. In the study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the threshold for regulatory concern. The dose of 1875 mg is adequate to represent the high exposure clinical scenario.
12.3 Pharmacokinetics
The pharmacokinetic properties of telaprevir have been eva luated in healthy adult subjects and in subjects with chronic hepatitis C. Following multiple doses of telaprevir (750 mg q8h) in combination with peginterferon alfa and ribavirin in treatment-naïve subjects with genotype 1 chronic hepatitis C, mean (SD) Cmax was 3510 (1280) ng/mL, Cmin was 2030 (930) ng/mL, and AUC8h was 22,300 (8650) ng∙hr/mL.
Absorption and Bioavailabilty
Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours. In vitro studies performed with human Caco-2 cells indicated that telaprevir is a substrate of P-glycoprotein (P-gp). Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telaprevir alone.
Effects of Food on Oral Absorption
The systemic exposure (AUC) to telaprevir was increased by 237% when telaprevir was administered with a standard fat meal (containing 533 kcal and 21 g fat) compared to when telaprevir was administered under fasting conditions. In addition, the type of meal significantly affects exposure to telaprevir. Relative to fasting, when telaprevir was administered with a low-fat meal (249 kcal, 3.6 g fat) and |
