imately 65% at the lowest dose (15 mg q12 h) to greater than 95% inhibition at the highest dose (100 mg q24h). Levels of pSTAT3 returned to control levels by the predose assessment on day 2 in all cohorts examined, with the possible exception of the 50-mg twice-daily group. A sigmoid I max /IC 50 model fitted to PK-PD data indicates that MK-0431 cytokine-induced pSTAT3 can be inhibited by INCB018424 with an ex vivo IC 50 value of 225 nM, slightly lower than that observed in the single-dose study (IC 50 = 254 nM), suggesting that accumulation of INCB018424 or its active metabolites was mini- mal. Because of the sparse nature of PD sampling following the multiple dosing, the steady-state PD parameters for each dose regimen were estimated using observed mean PK profiles at steady state and the PD parameters estimated from the single-dose study (Table VI).

As part of the pharmacodynamic evaluation, ARC was monitored in the study participants. The ARC counts were characterized by very large intersubject vari Cabozantinib
or as probably related to study medication. A third participant withdrew consent after 4 days of dosing with 50 mg bid INCB018424. Neutropenia of any severity grade was observed in 22.2% of placebo participants, 11.1% of participants at 50 mg qd, 66.6% of participants at 100 mg qd, 12.5% of par- ticipants at 15 mg bid, 33.3% of participants at 25 mg bid, and 66.6% of participants at 50 mg bid. These were generally transient and rapidly normal- ized following the last dose of study medication. In both the single- and multiple-dose studies, adverse events were, in general, mild to moderate in inten- sity and resolved quickly. The 1 episode of grade 4 neutropenia in the participant who received 50 mg bid was considered a dose-limiting toxicity.

The maximum tolerated dose was considered to be 25 mg when administered q12h and 100 mg when administered once daily. INCB018424 Pharmacokinetics and order chloroxine Pharmacodynamics Following Single Oral Dose Administration Following fasting, oral, single-dose administration of INCB018424 capsules, INCB018424 was absorbed rapidly, typically attaining peak plasma concentra- tions within 2 hours after administration for all doses. After attaining the C max , the INCB018424 plasma con- centrations declined in a multiphasic fashion with a mean terminal-phase disposition t 1/2 of approximately 3 hours for the 5 lowest doses. The mean terminal- phase disposition t 1/2 was slightly higher at 5 hours for the highest dose of 200 mg.

The oral dose clearance (CL/F) of INCB018424 was low (~20 L/h) and dose independent ( P = .895). The apparent volume of dis- tribution at the terminal phase (V z /F) was moderate (79-97 L) for INCB018424 following oral administra- tion of doses up to 100 mg. A summary of INCB018424 pharmacokinetic parameters following the single- dose administrations is provided in Table III. PHARMACOKINETICS AND  supplier chloroxine PHARMACODYNAMICS The mean INCB018424 C max and AUC increased in a linear, proportional manner to dose for the entire dose range. The power function regression analysis produced dose-proportionality equations of Following fasting, oral, single-dose administra- tion, INCB018424 demonstrated dose- and time- dependent inhibition of cytokine-induced pSTAT3 with maximal inhibition occurring 1 to 2 hours after  human anatomy administration for all doses, coincident with the C max . Maximal mean inhibition of pSTAT3 ranged from approximately 40% at the lowest dose (5 mg) to greater than 90% inhibition at the highest dose (200 mg). Levels of pSTAT3 returned to control levels by 24 hours in all treatments examined. Similar levels of inhibition were observed using either IL-6 or thrombopoietin as the cytokine stimulus. A sigmoid I max /IC 50 curve (Figure 2) may be fitted to the PK-PD data ( R 2 = 0.689), with the best-fit values (mean SD) for IC 50 and Hill coefficient as 254 314 nM and 1.00 1.29, respectively (the 95% CI ranges for IC 50 and Hill coefficient were 214-301 nM and 0.82-1.18, respectively).