metabolism of rux- olitinib and retain inhibitory activity against JAK1&2 to various degrees relative to the parent drug. Altogether, these metabolites accounted for approximately two- thirds of the total radioactivity of dose recovered in excreta and, along with the parent drug, represented > 90% of the drug-related material observed in circula- tion following the oral Marbofloxacin administration of a single dose of 14 C-ruxolitinib in healthy volunteers. 8 In vitro studies indicated that ruxolitinib was metabolized primarily by cytochrome P450 enzyme, CYP3A4. Two clinical studies were therefore con- ducted to evaluate the effect of CYP3A4 inhibition or induction, respectively, on the pharmacokinetics (PK) and pharmacodynamics (PD) of ruxolitinib, and the results are summarized in this report.

METHODS Study Population Men and women, 18 to 55 years of age, with a body mass index (BMI) of between 18 and 32 kg/m 2 were eligible for participation in the studies if they were judged to be in good health based on their medical history and phg inhibition of axitinib cytokine-stimulated pSTAT3 level. INCB018424 PD activity was consistent with the PK profile, and PHARMACOKINETICS AND PHARMACODYNAMICS there was no evidence of any PK-PD hysteresis in individual participants. A sigmoid I max /IC 50 model fitted to the PK-PD data indicates that cytokine- stimulated pSTAT3 was inhibited by INCB018424 with ex vivo IC 50 values of 254 and 225 nM, respec- tively, in the single- and multiple-dose studies, which were modestly lower than the in vitro IC 50 for INCB018424 (282 nM). This 10% to 20% difference between ex vivo and in vitro IC 50 is likely due to PD contribution from active metabolites. 15 Given that the pharmacodynamics following the first dose and at steady state were comparable, it can be concluded that there was minimal accumulation of either par- ent INCB018424 or active metabolites.

The criticality of JAK1 and JAK2 is evidenced from knockout mouse dataAK1 mice order norxacin showed perinatal lethality, 16 whereas JAK2 mice were not viable. 17 Therefore, round-the-clock inhibition of the JAK/STAT pathway is not desirable. Given the central role of JAK2 in hematopoiesis, a dose- dependent lowering of ARC, WBC, ANC, and plate- lets is expected with a JAK inhibitor. In the current study, a decrease in ANC was more noticeable fol- lowing bid dosing. One participant in the 50-mg bid cohort exhibited grade 4 neutropenia with a 12-day recovery, suggesting myelosuppression at this dose. Such an effect was not seen at lower bid doses or qd doses. All other cases of less severe neutropenia resolved within 12 to 24 hours of stopping medica- tion, suggesting that these mild cases are due to neutrophil margination as a result of blocking of IL-6 signaling. 18 The 50-mg bid regimen provided the highest average pSTAT3 inhibition of 65% as well as the highest I min and time over IC 50 (Table VI). Lack of myelosuppression at 100 mg qd suggests that this effect is driven by I ave and/or I min rather than I max .

Thus, the PD data in this study serve to provide a ceiling for hematologic tolerability in supplier norxacin healthy par- ticipants. Preclinical data in the myeloproliferative neoplasms (MPN) disease model indicate maximal efficacy associated with average inhibition of ~30% achieved with INCB018424 treatment (unpublished data). Together, these data provide a range of JAK/ STAT inhibition and hence dose regimen to be con- sidered for phase II/III studies for optimum efficacy and safety. Future publications will Black Death address the quantitative pharmacology aspects of pSTAT3 inhi- bition and disease end points. In conclusion, INCB018424 demonstrates rapid absorption, good bioavailability regardless of dosing in the fasted or fed state, dose-proportional systemic exposure, and minimal accumulation following repeat dosing, and it remains pharmacologically 1653 Downloaded from jcp.sagepub at Bobst Library, New York University on March 7, 2012 Ruxolitinib (INCB018424 Phosphate) in Healthy Volunteers