the results from drug- drug interaction studies conducted using a crossover comparison design. In vitro data suggest that ruxolitinib is primarily metabolized by CYP3A4 and not a substrate of P-glycoprotein (P-gp), an efflux transporter. Data from a 14 C-labeled ruxolitinib mass balance study indicated that intestinal absorption of ruxolitinib was nearly complete ( > 95%). 8 Therefore, the approximately 2-fold and 60% increase in the systemic exposure and dis- position half-life of ruxolitinib, respectively, with the HA-1077 coadministration of ketoconazole, a potent inhibitor of CYP3A4 and P-gp, was likely due to reduced rux- olitinib systemic clearance as a result of inhibition of CYP3A4 metabolism. The observed 2-fold increase in the PD activity following the ketoconazole cotreatment is consistent with the changes in ruxolitinib PK.

The modest increase in IC 50 for pSTAT3 inhibition in the presence of ketoconazole is also consistent with the expected decrease in contribution toward phar- macological activity from active metabolites. Coadministration of erythromycin, a relatively weaker CYP3A4 inhibitor compared to ketoconazole, resulted Ostarine
inistration on Ruxolitinib PK and PD (Study A, Cohort 2) Treatment Ruxolitinib PK Ruxolitinib Alone (n = 14) Ruxolitinib + Erythromycin (n = 14) GMR (90% CI) C max , nM t max , h t 1/2 , h AUC 0 , nM AUC 0, nM CL/F (L/h) 562 1.5 4.1 2130 2180 15.0 (27.4) (0.50-2.0) (32) (23.7) (25.5) (25.8) 609 1.0 4.5 2670 2760 11.8 (27.7) (0.50-1.5) (27) (27.4) (27.6) (25.8) 1.08 (0.95-1.25) 1.26 (1.16-1.36) 1.27 (1.17-1.38) Ruxolitinib PD AUCE 0-t , %inhibition I max, theo , % a 952 (16) 69 (11) 747 (24) 59 (18) 0.80 (0.70-0.92) 0.87 (0.79-0.96) All pharmacokinetic (PK) and pharmacodynamic (PD) parameter values are geometric mean (% coefficient of variation [CV]) except for t max , which is reported as median (range).

GMR, geometric mean ratio; CI, confidence interval (reference = ruxolitinib-alone buy epigallocatechin treatment). a As directly observed. Table IV The Effect of Rifampin Coadministration on Ruxolitinib PK and PD (Study B) Treatment Ruxolitinib Alone (Day 1, n = 12) Ruxolitinib + Rifampin (Day 13, n = 10) Ruxolitinib Alone (Repeat) (Day 34, n = GMR (90% CI) Ruxolitinib PK C max , nM t max , h t 1/2 , h All pharmacokinetic (PK) and pharmacodynamic (PD) parameter values are geometric mean (% coefficient of variation [CV]) except for t max , which is reported as median (range). Statistical analyses for PK and PD parameters were based on data from the 10 participants who completed the study through day 13 and the 8 participants who completed the study through day 34, respectively. GMR, geometric mean ratio; CI, confidence interval (reference = ruxolitinib-alone treatment). observed following the rifampin treatment. The PK profiles of ruxolitinib were comparable before the treatment of rifampin on day 1 and after the 3-week washout of rifampin on day 34 (Figure 4A).

Compared to the ruxolitinib-alone administration, pretreatment with rifampin caused a 10% decrease (GMR 90% CI, 0.75-1.1) in ruxolitinib PD effect as indicated by PD AUCE 0-t (Table IV). This minor dif- ference in ruxolitinib PD effect due to rifampin pre- treatment (Figure 4B) was unlikely to be clinically significant. With rifampin pretreatment, the purchase epigallocatechin geometric mean pSTAT3 inhibition IC 50 value, derived using ruxolitinib PK-PD data, decreased from 209 nM to 76 nM (66% reduction with GMR 90% CI of 0.15-0.78), suggesting that active metabolites likely made greater contributions to pSTAT3 inhibition relative to the parent compound with rifampin coadministration. The mean Hill coefficient ( g ) and I max, theo were essen- tially unchanged with rifampin convalescence pretreatment. Although this statistical analysis was based on the complete set of PD data from day 13 and day 34 of the study, the partial set of PD data that were collected over the first 7 Downloaded from jcp.sagepub at Bobst Library, New York University on March 7, 2012 represented more than 90% of the combine