decreasing concentrations, and the AUC from zero to infinity (AUC 0) was cal- culated as AUC 0 + C t / z . AUC last is AUC 0 computed to the last time point with a quantifiable concentra- tion. The oral dose clearance (CL/F) was estimated as Dose/AUC 0(single Ostarine  dose) or Dose/AUC  at pharmacokinetic steady state following repeat dos- ing), and the terminal-phase volume of distribution (V z /F) was estimated as Dose/[AUC 0z ] (single dose) or Dose  (at pharmacokinetic steady state following repeat dosing). All INCB018424 concentrations below quantitation limit (BQL = 1 nM) were substituted by a value of zero. The PK analysis was performed using WinNonlin 5.0.1 (Pharsight Corp, Mountain View, California). The PK-PD relationship was evaluated using sigmoid I max /IC 50 curve fitting with the following equation: I = I max, theo *C g / (C g + IC g 50 ), where I is the pSTAT3 inhibition by INCB01842 participants in cohort 2 (n = 9) received oral doses of 5, 25, and 100 mg INCB018424 or matching placebo. For the 6 dose levels (5-200 mg), participants were randomized to receive fasting oral administration of either the active Semagacestat treatment or placebo in a 2:1 ratio.

Dosing was administered after at least an 8-hour overnight fast, and a standardized meal was served approximately 3 hours after admin- istration. A washout period of 14 days (not less than 12 days) was instituted between treatment periods. 1645 Downloaded from order Finibax jcp.sagepub at Bobst Library, New York University on March 7, 2012 3  Part 2 of the study commenced upon completion of part 1 and used a 2-sequence, 2-period crossover design to evaluate the pharmacokinetic effect of a high-fat meal on a single oral dose of a tablet formu- lation of INCB018424 in healthy adult participants. Twelve of the 18 participants who completed part 1 were assessed for safety and then continued on to complete part 2 of the study. The participants were randomized to receive the 25-mg tablet formulation of INCB018424 either fasted or after a standardized high-fat, high-calorie meal, with the order of admin- istration randomized.

Using lavender-top (K 2 EDTA) The multiple-dose study was a randomized, double- blind, placebo-controlled tolerability and pharmacok- inetic study that enrolled 71 participants. Multiple doses of INCB018424 15 mg q12h, 25 mg q12h, 50 mg q 24h, 50 mg q12h, and 100 mg q24h were adminis- tered in the fasted state to successive cohorts of par- ticipants. There were 6 cohorts, 1 cohort per regimen as indicated above, except for 2 supplier Finibax cohorts that received 25 mg q12h treatment. In each cohort, participants were randomized to receive oral administration of either INCB018424 or placebo at a 3:1 ratio. A powder- in-capsule formulation was used in this study. Participants received study medication for 10 days with a single morning dose on day 10 for all cohorts. All morning doses were preceded by at least an 8-hour fast from food and a 1-hour fast from water and were followed by a fast from food and water for at least 1 hour postdose. All evening doses were preceded by at least a 3-hour fast from food and a 1-hour fast from water and were followed by a fast from food and water for at least 1 hour postdose.

Blood samples for deter- mination of plasma concentrations of INCB018424 were collected using lavender-top (K 2 EDTA) Vacutainer A predose urine sample and complete urine output from 0 to 12 and 12 to 24 hours postdose were col- lected on day 10 for determination of urine concentra- tions of INCB018424. The PD blood samples were drawn from participants at 0, 2, and 8 hours after INCB018424 administration on day 1 and day 10; pre- dose on days 2, 3, and 7; and on day 12 (48 hours after the last dose of INCB018424). In some cohorts, serial determination of white blood cell (WBC) and reproducible absolute neutrophil (ANC) were determined prior to dosing and 4, 8, 12, 16, and 24 hours following dosing on day 10 (following the last dose of study medication). Analytical Methods Pharmacoki