plasma protein binding of about 97%, INCB018424 does not appear to dis- tribute extensively in the body as indicated by its 1652 J Clin Pharmacol 2011;51:1644-1654 moderate apparent volume of distribution. The short elimination half-life of INCB018424 appears to be driven by a relatively small volume of distribution since the oral clearance is relatively low at about 20% of hepatic blood flow. Consistent with good solubility of mercaptopurine INCB018424, dosing with meal has lit- tle effect on INCB018424 oral bioavailability. Following repeated dosing for 10 consecutive days, plasma concentrations of INCB018424 did not accu- mulate appreciably, as predicted by its short half- life, nor was there any evidence of autoinduction or inhibition of clearance.

Renal excretion of unchanged INCB018424 was negligible (<0.5%), and multiple metabolites were found in the plasma samples (data to be presented in a future Masitinib publication), indicating that INCB018424 was eliminated primarily by metabolism. INCB018424 PD was investigated usint bioequivalence criteria requiring the 90% confidence limits of the geometric mean relative bioavailability to lie entirely within 80% to 125% for the 12 partici- pants in this study. Therefore, INCB0018424 tab- lets can be administered without regard to meals. Although the relative bioavailability of tablet ver- sus capsule formulation was not investigated using a specific crossover comparison design, the data from the 12 participants who received both the tablet and capsule formulations indicated that the dose- normalized geometric mean AUC ratio of tablet versus capsule was 0.76.

Thus, the limited data in this The pharmacokinetics of INCB018424 following the first dose and at the steady state were similar to those observed in the single-dose study as order phenformin described above. INCB018424 plasma concentration-time profiles on day 10 of the dosing are shown in Figure 3, with the corresponding pharmacokinetic parameters summa- rized in Table V. The trough plasma concentrations of INCB018424 following q12h or q24h regimens for 10 consecutive days are depicted in Figure 4. The serial trough plasma concentrations indicate that INCB018424 reached pharmacokinetic steady state by day 2 for all regimens, consistent with the relatively short terminal half-life of INCB018424 of about 3 hours. There were no significant changes in observed pharmacokinetic parameters on day 10 versus day 1 for all regimens. INCB018424 accumu- lation following q12h administration (~10%) was negligible compared to the variability in systemic exposure observed in this study (~30%). The mean INCB018424 C max and AUC increased in a linear proportional manner to dose for both the three q12h regimens and the two q24h regimens.

For the three q12h regimens at the steady state, the power function regression analysis Vesalius produced dose- proportionality equations for C max = 203 Dose 0.947 ( P = .703 for = 1) and AUC 0-12 h = 29.2 Dose 1.14 ( P = .286 for = 1), which indicates that the steady- state C max and AUC 02 h increased approximately linearly proportional to the dose over supplier phenformin the range of 15 mg to 50 mg q12h, and the exponent, , of the power function was not statistically significantly different from 1 for C max or AUC 02 h . Table IV Food Effect on INCB018424 Single-Dose Pharmacokinetics in Healthy Participants To estimate the steady-state urine recovery of INCB018424, the urine samples from the 100-mg q24h regimen were assayed by an exploratory LC/ MS/MS method. On average, 0.11% of the adminis- tered dose was recovered in urine as unchanged INCB018424 over 1 steady-state dosing interval (range, 0.031%-0.39%, n = 9). Given the low urinary recovery of the parent compound, a GLP assay for determination of INCB018424 concentrations in urine samples was not developed. The pharmacodynamics of INCB018424 following multiple oral dosing was also similar to that observed following the corresponding single oral dose. Maximal inhibition of cytokine-induced pSTAT3 ranged