A randomized dose-escalation study to assess the safety, tolerability, and pharmacokinetics of ruxolitinib (INC424) in healthy Japanese volunteers

Abstract

Ruxolitinib (INC424), a potent and selective oral Janus kinase 1 and 2 inhibitor, was recently approved by the US food and drug administration for the treatment of intermediate or high-risk myelofibrosis. The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been extensively evaluated in healthy subjects and patients. The present study is the first to investigate the PK and tolerability of ruxolitinib in the Japanese population. Forty subjects were randomized to receive single (10-100 mg) and multiple (10 and 25 mg every 12 h) doses of ruxolitinib or placebo. Cohorts were sequentially enrolled based on the outcome of safety assessments. Ruxolitinib was rapidly absorbed, and its exposure increased dose proportionally up to 100 mg. The half-life of ruxolitinib was approximately 3 h, and drug accumulation was not observed after repeated dosing at a 12-h dosing interval. Decreasing absolute neutrophil counts were observed in five Japanese subjects treated once (100 mg, n = 1) or twice (10 mg, n = 3; 25 mg, n = 1) daily. These events were manageable and reversible upon drug discontinuation. Orally administered ruxolitinib was well tolerated in healthy Japanese volunteers. There were no apparent differences in the safety or PK of ruxolitinib between Japanese and non-Japanese subjects.

The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

“…This hypothesis is fully supported by the fact that other drugs targeting the IL-6 pathway, such as the mAbs tocilizumab, sarilumab, and sirukumab, have been shown to reduce exposure of coadministrated drugs like simvastatin, midazolam, or omeprazole (Schmitt et al, 2011;Zhuang et al, 2015;Lee et al, 2017). Moreover, ruxolitinib concentrations required to counteract IL-6mediated suppression of P450s and drug transporters in vitro are in the 1.0-1.2 mM range, which is close to the range of ruxolitinib maximum plasma concentrations (C max ; 0.59-1.29 mM) reached in patients treated with the JAK inhibitor (Ogama et al, 2013). In addition, ruxolitinib in vitro effects toward IL-6-related P450 and transporter repression seem to be not transient, i.e., they lasted at least 72 hours in cultured human hepatocytes.…”

Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions

“…However, we have previously reported that short-term suppression of either pSTAT5 or JAK1/2 activity can restore the apoptosis anticancer barrier and reduce mammary tumor risk in mouse models [ 11 ]. Ruxolitinib is an FDA-approved small molecule inhibitor of JAK1/2 for the treatment of myelofibrosis and polycythemia vera; it has minimal significant side effects following short-term use in healthy individuals [ 63 – 66 ]. Therefore, we asked whether short-term ruxolitinib treatment could prevent mammary tumors in early lesion-bearing mice on risperidone.…”

Dual inhibition of JAK1/2 kinases and BCL2: a promising therapeutic strategy for acute myeloid leukemia

“…Furthermore, 80% (156/195) of samples tested demonstrate IC 50 values for Rux + Ven <0.5 μM. Previously reported levels of each drug in plasma (ruxolitinib C max for 10 mg BID: 0.562 μM [5]; venetoclax C max for 400 mg QD: 2.51 μM [6]) suggest effective combination concentrations would be achievable in patients.…”