ABSTRACT
Vaniprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease. The aim of these double-blind, placebo-controlled phase I studies was to evaluate the safety and pharmacokinetics of vaniprevir in healthy male volunteers. The primary objective for both studies was the safety and tolerability of vaniprevir. Single-dose and steady-state pharmacokinetics were also assessed. In both studies, there was no apparent relationship between the frequency or intensity of adverse events and vaniprevir dose. At single doses >20 mg, the plasma area under the curve (AUC)0-∞ and maximum concentration (Cmax ) increased in a greater-than-dose-proportional manner. The geometric mean ratios (GMRs; fed/fasted) were 1.22 and 0.79 for AUC0-∞ and Cmax , respectively. Following multiple doses, GMR accumulations for AUC0-12h and Cmax (day 14/day 1) ranged from 1.53 to 1.90 and from 1.41 to 1.92, respectively. These data support the use of vaniprevir with peginterferon and ribavirin in patients with HCV infection.
Subject(s)
Health , Indoles/administration & dosage , Indoles/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Cyclopropanes , Dose-Response Relationship, Drug , Fasting , Humans , Indoles/blood , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Male , Proline/analogs & derivatives , Sulfonamides , Young AdultABSTRACT
Ambient temperature has been shown to affect energy metabolism in field situations. Therefore, we assessed the effect of a short exposure to the thermoneutral zone, i.e., 27 degrees C (81 degrees F), in comparison to the usual ambient temperature of 22 degrees C (72 degrees F), on energy expenditure (EE), substrate oxidation, and energy intake (EI) in a controlled situation. Subjects, i.e., women (ages 22+/-2 years, BMI 22+/-3, 28+/-4% body fat), stayed in a respiration chamber three times for 48 h each: once at 22 degrees C, and twice at 27 degrees C in random order, wearing standardized clothing, executing a standardized daily-activities protocol, and being fed in energy balance (EB). During the last 24 h at 22 degrees C, and once during the last 24 h at 27 degrees C, they were fed ad libitum. At 27 degrees C, compared to at 22 degrees C, EE was 8.9+/-1.3 MJ/day vs. 9.9+/-1.5 MJ/day (P<.001) due to decreases in diet-induced thermogenesis (DIT) and activity-induced energy expenditure (AEE) (P<.01); respiratory quotient (RQ) had increased (P<.05); core (P<.05) and skin (P<.001) temperatures had increased. During ad lib feeding, EI was 90-91% of EE (P=.9), due to changes in energy density (ED) of the food choice (P<.01), and related to changes in body temperature and EE (P<.001). Thus, at 27 degrees C, compared to 22 degrees C, energy metabolism was reduced by reductions in DIT and in AEE, while RQ was increased. Reduction in EI was primarily related to body temperature changes and secondarily to changes in EE.
