Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting.

Evaluation of Clinical Cardiac Safety of Itacitinib, a JAK1 Inhibitor, in Healthy Participants.

Itacitinib is a JAK1-selective inhibitor in phase 3 development in graft-versus-host disease. A post hoc electrocardiogram (ECG) analysis and a plasma concentration-QTc (C-QTc) analysis were performed to assess cardiac safety using data from the first-in-human itacitinib study. The study included 2 cohorts of 12 healthy participants each in an interleaving dosing design with single doses of 10-300 mg or placebo; 500 and 1000 mg doses were subsequently added with 12 participants randomized to itacitinib or placebo.

Effect of Itraconazole or Rifampin on Itacitinib Pharmacokinetics When Administered Orally in Healthy Subjects.

Itacitinib is a potent, selective JAK-1 inhibitor currently in phase 3 development for the treatment of acute and chronic graft-versus-host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily eliminated via metabolism by cytochrome P-450 (CYP)3A4 with minimal renal elimination. A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole or the strong CYP3A4 inducer rifampin on the pharmacokinetics of itacitinib in healthy volunteers.

Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients.

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 effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) 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.

The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers.

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.