The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers

Abstract

Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double-blind, randomized, and placebo-controlled studies were conducted to evaluate single ascending doses of 1-20 mg and multiple ascending doses of 2-20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi-exponential fashion. Baricitinib demonstrates dose-linear and time-invariant pharmacokinetics, with low oral-dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼2 L/h. The effect of a high-fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment-related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose-related decline in absolute neutrophil count was seen with baricitinib.

Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: A 52-week, randomized, single-blind, extension study

“…Hemoglobin remained stable during the extension period in both treatment groups. The reduction in neutrophils observed in the extension period was also observed in the first 12 weeks of the study [5] as well as in other studies of baricitinib [8,9], with similar shifts in CTCAE grade observed, and prior data indicate that transient margination of neutrophils contributed to this observation [21]. Declines in lymphocyte count were observed in some patients during the extension period.…”

Trisomy 21 consistently activates the interferon response

“…Importantly, several JAK inhibitors are either approved or being tested in clinical trials for the treatment of several conditions associated with DS –albeit in the typical population–, including myeloproliferative, inflammatory and autoimmune disorders, as well as leukemia (Padron et al, 2016; Spaner et al, 2016; Tefferi et al, 2011; Quintás-Cardama et al, 2010; Shi et al, 2014; Keystone et al, 2015; Jabbari et al, 2015). It should be noted, however, that the dose limiting toxicities of JAK inhibitors, like ruxolitinib, are anemia and thrombocytopenia (McKeage, 2015; Plosker, 2015).…”

Efficacy and safety of baricitinib for active rheumatoid arthritis in patients with an inadequate response to conventional synthetic or biological disease‑modifying anti‑rheumatic drugs: A meta‑analysis of randomized controlled trials

“…According to Fridman et al (7) and Shi et al (8), baricitinib is an novel, oral low-molecular- weight JAK inhibitor with good selectivity for JAK1 [concentration leading to 50% inhibition (IC 50 )=5.7 nM] and JAK2 (IC 50 =5.9 nM), and less selectivity for JAK3 (IC 50 >400 nM) or Tyk2 (IC 50 =53 nM), and the kidneys are considered to be the principal organ to eliminate baricitinib. Shi et al (8), Kubo et al (9) and Emery et al (10) reported that baricitinib inhibits the phosphorylation of STATs induced by various cytokines in the whole blood, and results in a transient change in neutrophil and lymphocyte counts. A previous meta-analysis suggested that the use of the JAK inhibitor tofacitinib is associated with manageable safety and increased clinical efficacy in the short-term compared with placebo (11).…”