ir 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/h 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
Hepatic Impairment
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.
Renal Impairment
After administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl less than 30 mL/min), the LS means of telaprevir Cmax and AUCinf were increased by 3% and 21%, respectively, compared to healthy subjects.
Gender
The effect of subject gender on telaprevir pharmacokinetics was eva luated using population pharmacokinetics of data from clinical trials of telaprevir. No dose adjustments are deemed necessary based on gender.
Race
Population pharmacokinetic analysis of telaprevir in HCV-infected subjects indicated that race had no apparent effect on the exposure to telaprevir.
Geriatric Use
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.
Pediatric Use
The pharmacokinetics of INCIVEK in pediatric patients have not been eva luated.
Drug Interactions
In vitro studies indicated that telaprevir is a substrate and inhibitor of CYP3A4 and a substrate and inhibitor of P-gp. No inhibition by telaprevir of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 isozymes was observed in vitro. In vitro studies also suggest that telaprevir has a low potential to induce CYP2C, CYP3A, or CYP1A. Therefore, clinical studies were conducted to eva luate the effect of drugs that can affect or be affected by telaprevir during co-administration (Tables 6 and 7).
Table 6 Drug Interactions: Summary of Pharmacokinetic Parameters for Telaprevir in the Presence of Co-administered Drugs*
|
Drug |
Dose and Schedule |
N |
Effect on Telaprev
|
|
