ack G. Shi, PhD, Xuejun Chen, PhD, Thomas Emm, BS, Peggy A. Scherle, PhD, Ryan F. McGee, BS, Yvonne Lo, MS, Robert R. Landman, BS, Edward G. McKeever Jr., BS, Naresh G. Punwani, PhD, William V. Williams, MD, and Swamy Yeleswaram, PhD MDV3100 Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neo- plasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose rux- olitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and MK-8669 erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC 0- ) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of inter- leukin (IL)-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed.

Pre- treatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC 0- by 71% while reability, which is typical for phase I studies with intensive blood sampling. Nevertheless, it appears that active treated groups had a decline in ARC from day 7 until day 12, which was followed by a recovery to baseline by day 17. The decreases were order altretamine minimal for the 15-mg twice-daily group and appeared to sta- bilize between days 10 and 12 for all active-treated groups. Increases to above baseline were noted at day 24 for all active-treated groups. The placebo group remained essentially unchanged with only very slight increases noted following day 10. A plot of the mean ARC value over time is presented in Figure 5. In addition, for some cohorts, ANC and WBC were determined with frequent sampling on day 10. The ANC data are shown in Figure 6. A drop in ANC was seen for all twice-daily dosing cohorts by day 2 of dosing but was less pronounced or absent for the once-daily cohorts. On day 10, with serial sampling for the bid cohorts, the low ANCs were seen to reverse back toward the predose baseline within 24 hours following the last dose. For the 100-mg once- daily cohort (the only once-daily dosing cohort for which serial ANCs were determined), a slight decrease was seen on day 2, but the values were otherwise in the normal range.

On day 10, a revers- ible decrease in ANC was seen that peaked approxi- mately 8 hours following dosing and reversed to This report describes the first in-human studies of supplier altretamine INCB018424 following single and multiple oral dose administrations. The investigational drug was gener- ally safe and well tolerated. The treatment-emergent adverse events from each active treatment group were similar in the single-dose study and were slightly higher in the multiple-dose study compared to those observed for the corresponding placebo group. All adverse events were resolved prior to study conclusion. An episode of grade 4 neutropenia established 25 mg q12h as the maximum tolerated dose, whereas for qd dosing, the highest dose (100 mg q24h) was well tolerated. 0 0 10 20 Study Day Figure 5. The time course of absolute reticulocyte counts (ARC; mean SE) during the multiple-dose study. Panel A: BID doses; Panel B: placebo and QD doses. Consistent with the BCS class I drug designation, data from the current studies indicate that INCB0- 18424 is rapidly absorbed in humans.

Assuming complete oral dose absorption and negligible first- pass metabolism at the gut wall, oral availability may be expressed as Q/(Q + Cl/F), 14 where Q is the liver blood flow of 1.24 L/h/kg for an average healthy adult. Thus, the mean systemic availability is esti- mated to be about 80% for INCB018424 following the administration of the capsule Ptolemy formulation in the 2 studies. INCB018424 systemic exposures are pro- portional to dose over the range of 5 to 200 mg. This is consistent with concentration-independent per- meability in caco-2 cells (data not shown), suggest- ing lack of interaction with transporters in absorption.