INCB018424 Pharmacokinetics The effect of food on INCB018424 pharmacokinetics was evaluated in healthy participants who were administered a single tablet of 25 mg nebivolol INCB018424 while fasting or immediately after a standardized high- fat, high-calorie meal. The comparative INCB018424 1649 Figure 2. The pharmacokinetic-pharmacodynamic relationship established from INCB018424 single-dose study. The solid line and dashed lines are the best-fit curve and 95% predictive inter- val, respectively. pharmacokinetic parameters are summarized in Table IV.

Administration of the 25-mg tablets with a high-fat, high-calorie meal slowed the absorp- tion of INCB018424 from the 25-mg tablets, pro- longing the median t max from 1.0 to 2.5 hours and lowering the geometric mean C max by 24.3% com- pared to fasted  Vinflunine administration. However, adminis- tration with food showed little effect on INCB018424 AUC ( P = .322). In fact, comparison of the INCB018424 AUC between the fasted and fed tablet treatments met the stric4 expressed as a percent decrease of pSTAT3 level compared to the baseline value observed at predose (t = 0), C is the plasma concentration of INCB018424, IC 50 is the INCB018424 concentration at which I =  max,theo , is the Hill coefficient, and I max,theo is the maximum theoretical inhibition achievable at C = . The PK-PD curve fitting was performed using Prism 3.0 (GraphPad Software, La Jolla, California), with the boundary for I set between 0% (at C = 0) and 100% (at C = ), and all data points were included as observed. 1647 Downloaded from jcp.sagepub at Bobst Library.

New York University on March 7, 2012 The participants in part 2 form a subset population purchase Imatinib from part 1 of the single-dose study. Statistical Evaluation For the rising single-dose study, the log-transformed pharmacokinetic parameters were compared among the dose groups using a 2-factor analysis of variance (ANOVA) with factors for subject and dose. For the multiple-dose study, the log-transformed pharmacok- inetic parameters were compared among the dose groups using a 1-factor ANOVA with the factor for dose. The dose proportionality of INCB018424 C max and AUC was evaluated by using a power function regression (eg, AUC 0= Dose ). Dose-dependent parameters (C max , C min , AUC 0, and AUC  were dose normalized before statistical comparisons were made.

For the food effect study, the log-transformed pharma- cokinetic parameters were compared between the treatments using an ANOVA for a crossover study design with fixed effects for sequence, treatment, and period and a random effect for subject nested within sequence. In addition, the geometric mean relative bioavailability and 90% order Imatinib confidence intervals (CIs) for C max , AUC 0 , and AUC 0were calculated based on the adjusted means (least square means) from the ANOVA. All statistical analyses were performed using SAS version 9.1 (SAS Institute, Inc, Cary, North Carolina). Pharmacodynamic variables were summa- rized using descriptive statistics and graphics. RESULTS Study Population and Safety Analysis The baseline demographics of the study participants are summarized in Table II. In the rising single-dose study, 1 participant with- drew consent, 1 participant was lost to follow-up, and 3 participants withdrew prematurely because of adverse events, including the 1 case of a serious adverse event of hyponatremia following dosing with 5 mg INCB018424 in a participant with a his- tory of low sodium levels, judged unrelated to study drug; 1 case of nonsustained ventricular tachycardia (7-beat run) following placebo dosing; and 1 case of nonsustained ventricular tachycardia (4-beat run) following dosing with 5 mg INCB018424. All these 5 participants were replaced. There was no dose dependency for the frequency of adverse events as a whole or of any particular adverse event. The most frequent adverse events were William Harvey headache (13.0% over- all incidence) occurring in participants receiving placebo, 5 mg INCB018424, or 100 mg INCB018424;