No abstract

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo-controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 C(max) by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers.

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and 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 interleukin (IL)-6-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC(0-∞) by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin.

Background Pathogenesis of atopic dermatitis (AD) involves the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. A cream formulation of ruxolitinib, a potent selective JAK1/JAK2 inhibitor, was developed for topical delivery. Method Pharmacokinetic data were obtained from three double-blind, vehicle-controlled studies in patients with AD: a phase II study with ruxolitinib cream 0.15%, 0.5%, or 1.5% once daily or 1.5% twice daily (BID), and two phase III studies with 0.75% or 1.5% BID. Effects of baseline characteristics on pharmacokinetics were examined. Correlations were attempted between plasma concentrations and change in hematological parameters over time. Results Ruxolitinib plasma concentrations at steady-state (C ss ) increased with cream strength in a less-than-dose-proportional manner. In the phase III studies, overall mean (standard deviation [SD]) C ss after ruxolitinib cream 0.75% and 1.5% BID (23.8 [35.0] and 35.7 [55.0] nM) were a fraction of the half-maximal inhibitory concentration for thrombopoietin-stimulated phosphorylated STAT3 inhibition (281 nM), a JAK/STAT signaling marker. Three covariates were identified for C ss : dose, percent body surface area (%BSA) treated, and baseline Investigator's Global Assessment score. Mean (SD) bioavailability of ruxolitinib cream 1.5% BID was 6.22% (7.66%). There were no correlations between C ss and any hematological changes except for a transient increase in platelets at week 2. Conclusions Plasma ruxolitinib concentrations after treatment with topical ruxolitinib cream in patients with up to 20% BSA affected by AD are not expected to lead to systemic plasma concentrations that may be associated with adverse effects commonly associated with oral JAK inhibitors. ClinicalTrials.gov NCT03011892; NCT03745638; NCT03745651.

Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single-dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 × 10(9) /L and 150 × 10(9) /L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.