Telaprevir clinical pharmacology

# Clinical Pharmacology

## Pharmacodynamics

### ECG Evaluation
The effect of telaprevir 750 and 1875 mg on QTc interval was evaluated in a double-blind, double-dummy, randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 44 subjects. In the trial 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.

## Pharmacokinetics
The pharmacokinetic properties of telaprevir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following multiple doses of telaprevir (750 mg every 8 hours) in combination with peginterferon alfa and ribavirin in treatment-naive 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) nghr/mL.
Telaprevir total exposure (AUC24h,ss) was similar regardless of whether the total daily dose of 2250 mg was administered as 750 mg every 8 hours or 1125 mg twice daily.

### Absorption and Bioavailability
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 a high-fat meal (928 kcal, 56 g fat), the systemic exposure (AUC) to telaprevir was increased by approximately 117% and 330%, respectively. Doses of INCIVEK were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat in the Phase 3 trials. Therefore, INCIVEK should always be taken with food (not low fat).

### Distribution
In vitro, within a concentration range of 0.1 M (68 ng per mL) to 20 M (13600 ng per mL), telaprevir is approximately 59% to 76% bound to plasma proteins. Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding is concentration dependent, decreasing with increasing concentrations of telaprevir. After oral administration, the typical apparent volume of distribution (Vd/F) was estimated to be 252 L, with an inter-individual variability of 72%.

### Metabolism
Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated-oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the -ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir. In vitro studies using recombinant human cytochrome P450 (CYP) isoforms indicated that CYP3A4 was the major isoform responsible for CYP-mediated telaprevir metabolism. In vitro studies using recombinant aldo-ketoreductases indicated that these and potentially other reductases are also responsible for the reduction of telaprevir. Other proteolytic enzymes are also involved in the hydrolysis of telaprevir. These non-CYP mediated pathways of metabolism likely play a major role after multiple dosing of telaprevir.

### Elimination
Following administration of a single oral dose of 750 mg 14C-telaprevir in healthy subjects, 90% of total radioactivity was recovered in feces, urine and expired air within 96 hours post-dose. The median recovery of the administered radioactive dose was approximately 82% in the feces, 9% in exhaled air and 1% in urine. The contribution of unchanged 14C-telaprevir and the R-diastereomer of telaprevir towards total radioactivity recovered in feces was 31.9% and 18.8%, respectively. After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4 L per hour with an inter-individual variability of 27.2%. The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours.

### Specific Populations
Steady-state exposure to telaprevir was reduced by 46% in HCV-negative subjects with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. The appropriate dose of INCIVEK in HCV-infected subjects with moderate or severe hepatic impairment has not been determined and therefore INCIVEK is not recommended in these populations.
Steady-state exposure to telaprevir was reduced by 15% in HCV-negative subjects with mild hepatic impairment (Child-Pugh Class A) compared to healthy subjects. Dose modification of INCIVEK is not required when administered to subjects with mild hepatic impairment. In previously treated subjects who had compensated liver disease and were treated with INCIVEK in combination with peginterferon alfa and ribavirin, subjects with cirrhosis had similar PK parameters compared to those without cirrhosis.
After administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl less than 30 mL per min), the LS means of telaprevir Cmaxand AUCinf were increased by 3% and 21%, respectively, compared to healthy subjects.
The effect of subject gender on telaprevir pharmacokinetics was evaluated using population pharmacokinetics of data from clinical trials of telaprevir. No dose adjustments are deemed necessary based on gender.
Population pharmacokinetic analysis of telaprevir in HCV-infected subjects indicated that race had no apparent effect on the exposure to telaprevir.
Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19-70 years) investigated (35 subjects 65 years of age and older), subject age did not have a clinically relevant effect on the exposure to telaprevir.
The pharmacokinetics of INCIVEK in pediatric patients have not been evaluated.