The Pharmacokinetics, Pharmacodynamics, and Safety of Orally Dosed INCB018424 Phosphate in Healthy Volunteers

Shi, Jack G.; Chen, Xuejun; McGee, Ryan; Landman, Robert; Emm, Thomas; Lo, Yvonne; Scherle, Peggy; Punwani, Naresh; Williams, William V.; Yeleswaram, Swamy

doi:10.1177/0091270010389469

Cited by 145 publications

(164 citation statements)

References 17 publications

Supporting

Mentioning

148

Contrasting

Unclassified

Order By: Relevance

“…Increasing inhibitor concentration was accompanied by reduced phosphorylation of the JAK2 fusion protein, ERK, STAT5 and AKT ( Figure 1C). Together with previous findings on ruxolitinib pharmacology (25 mg dose gives a C max of 934 nM), 15 our data therefore, suggest that effective inhibition of JAK2 fusion proteins would be readily obtainable in vivo.…”

Section: Resultssupporting

confidence: 87%

Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements

et al. 2012

View full text Add to dashboard Cite

Section: Resultssupporting

confidence: 87%

Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements

et al. 2012

View full text Add to dashboard Cite

“…Ruxolitinib was the more efficacious inhibitor across both systems and inhibited Ն50% of reactivation at steady-state concentrations or at the maximum concentration (C max ) in vivo (Fig. 3, shaded boxes) (28,29).…”

Section: Figmentioning

confidence: 97%

Ruxolitinib and Tofacitinib Are Potent and Selective Inhibitors of HIV-1 Replication and Virus ReactivationIn Vitro

Gavegnano

Detorio

Montero

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The JAK-STAT pathway is activated in both macrophages and lymphocytes upon human immunodeficiency virus type 1 (HIV-1) infection and thus represents an attractive cellular target to achieve HIV suppression and reduced inflammation, which may impact virus sanctuaries. Ruxolitinib and tofacitinib are JAK1/2 inhibitors that are FDA approved for rheumatoid arthritis and myelofibrosis, respectively, but their therapeutic application for treatment of HIV infection was unexplored. Both drugs demonstrated submicromolar inhibition of infection with HIV-1, HIV-2, and a simian-human immunodeficiency virus, RT-SHIV, across primary human or rhesus macaque lymphocytes and macrophages, with no apparent significant cytotoxicity at 2 to 3 logs above the median effective antiviral concentration. Combination of tofacitinib and ruxolitinib increased the efficacy by 53-to 161-fold versus that observed for monotherapy, respectively, and each drug applied alone to primary human lymphocytes displayed similar efficacy against HIV-1 containing various polymerase substitutions. Both drugs inhibited virus replication in lymphocytes stimulated with phytohemagglutinin (PHA) plus interleukin-2 (IL-2), but not PHA alone, and inhibited reactivation of latent HIV-1 at low-micromolar concentrations across the J-Lat T cell latency model and in primary human central memory lymphocytes. Thus, targeted inhibition of JAK provided a selective, potent, and novel mechanism to inhibit HIV-1 replication in lymphocytes and macrophages, replication of drug-resistant HIV-1, and reactivation of latent HIV-1 and has the potential to reset the immunologic milieu in HIV-infected individuals.

show abstract

“…The pharmacokinetics of ruxolitinib was evaluated in healthy volunteers in 2 double-blind, randomized, placebo-controlled studies (16). The drug showed good oral bioavailability independently of fasted or fed state, doseproportional systemic exposure with a small volume of distribution, and an $3-hour plasma half-life.…”

Section: Pharmacokinetics/pharmacodynamicsmentioning

confidence: 99%

Ruxolitinib: The First FDA Approved Therapy for the Treatment of Myelofibrosis

Mascarenhas

Hoffman

2012

Clinical Cancer Research

188

114

View full text Add to dashboard Cite

The BCR-ABL1-negative myeloproliferative neoplasms (e.g., essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains. Hematopoietic stem cell transplant offers the only potential for cure in a minority of eligible patients, leaving a serious unmet need for improved therapies. Recent advances in our understanding of the pathogenetic mechanisms underlying these diseases have led to an explosion of clinical trials evaluating novel therapies. The discovery of an activating mutation in the Janus-activated kinase 2 (JAK2) gene provided a therapeutic target to downregulate this activated signaling pathway, which influences the phenotype of these diseases. Ruxolitinib (Jakafi; Incyte) is a small-molecule inhibitor of JAK1/2 that has proved to be effective at reducing splenomegaly and ameliorating symptoms in myeloproliferative neoplasms. Based on the results of 2 pivotal randomized phase III clinical trials, ruxolitinib has become the first therapeutic to be approved by the U.S. Food and Drug Administration for treatment of patients with myelofibrosis. Ruxolitinib offers a well-tolerated oral therapeutic option for patients with myelofibrosis with symptomatic splenomegaly and debilitating disease-related symptoms, but it does not seem to be effective at eliminating the underlying hematological malignancy.

show abstract

The Pharmacokinetics, Pharmacodynamics, and Safety of Orally Dosed INCB018424 Phosphate in Healthy Volunteers

Cited by 145 publications

References 17 publications

Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements

Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements

Ruxolitinib and Tofacitinib Are Potent and Selective Inhibitors of HIV-1 Replication and Virus ReactivationIn Vitro

Ruxolitinib: The First FDA Approved Therapy for the Treatment of Myelofibrosis

Contact Info

Product

Resources

About