P3A4 and P-gp. 12,13 Given that ruxolitinib is not a substrate of P-gp, rifampin is not expected to affect its PK through P-gp induction. The observed 71% decrease in AUC and almost 50% decrease in the half-life of ruxolitinib following rifampin treatment, therefore, were most likely attributable to increased ruxolitinib metabolic clearance through CYP3A4 FTY720 induction. To better understand the apparent disconnect between the PK (71% decrease in plasma AUC) and PD (10% decrease in pSTAT3 inhibition AUCE), plasma concentrations of ruxolitinib metabolites were determined in samples obtained following dosing of ruxolitinib with and without coadministration of rifampin.

Overall, the AUCs of metabolites were unchanged in the presence of rifampin compared SB 216763 to administration of ruxolitinib alone. However, the sum total AUC of metabolites relative to parent increased by more than 2-fold. In other words, the PD contribution of metabolites was preserved with rifampin coadminis- tration. This was despite an apparent induction of clear- ance of metabolites, as suggested by the decrease in the terminal half-life values of the metabolites. Estimation
ifampin pretreatment, the sum total of IC 50 -adjusted percent AUC from the major metab- olites increased from 13% to 31%, indicating a greater than 2-fold increase in contribution to the pharmacologi- cal activity from the metabolites relative to the parent drug following the rifampin coadministration. Figure 4. Ruxolitinib plasma concentrations (A) and purchase HA-1077 corresponding pSTAT3 inhibitions (B) in healthy participants receiving 50-mg ruxolitinib tablets with or without concomitant rifampin medication (data presented as mean SE). 4 hours on day 1 was essentially identical to day 34 (data not shown). Effect of Concomitant Administration of Rifampin on the Pharmacokinetics of Ruxolitinib Metabolites The pharmacokinetics of the 8 metabolites of ruxolitinib were analyzed in study B. Listed in Table V are the PK parameters for the 5 major metabolites, defined in this report as those with observed plasma AUC values equal to or greater than 10% of that of the parent, either before or after rifampin treatment.

These 5 metabolites Safety All doses of ruxolitinib were generally safe and well tolerated order HA-1077 when given alone and in combination with ketoconazole, erythromycin, or rifampin. In both stud- ies, there were no serious adverse events or discon- tinuations from the studies due to adverse events, except for 1 participant who withdrew prematurely for an adverse event of nausea, which was assessed as mild in intensity, during the treatment with rifampin only in study B. There were no trends or clinically relevant changes noted in clinical laboratory, vital sign, or electrocardiographic findings following the administration of study medications. The safety data of ruxolitinib in healthy volunteers following single- and multiple-dose administrations were reported ear- lier in a separate publication. 7 DISCUSSION As a BCS (Biopharmaceutical Classification System) class 1 drug, ruxolitinib was rapidly absorbed and typically attained peak plasma concentrations within 1.5 hours following administration as tablets, with or without coadministration of a CYP3A4 inhibitor or Pharmacokinetic (PK) parameter values are geometric mean (% coefficient of variation [CV]) except for t max , which is reported as median (range). inducer.

With administration of ruxolitinib alone, the observed PK and PD profiles of ruxolitinib were paroxysm com- parable to those reported previously from the first-in- human single-dose PK study conducted in healthy volunteers. 7 Although the demographic ratios regard- ing gender and ethnicity were imbalanced for the studies reported here, neither of these 2 factors was expected to show a well-defined or clinically mean- ingful effect on drug dispositions mediated by CYP3A4 metabolism. 10,11 Furthermore, any potential ethnic or gender difference in ruxolitinib pharmacokinetics is unlikely to affect significantly