AB0364 Pharmacokinetics, safety, and tolerability of asp015k, a novel janus kinase inhibitor, in healthy volunteers
Authors: T. Zhu, T. Sawamoto, U. Valluri, M. Lewand, Y. Cao, S. Swan, K. Lasseter, M. Matson, J. Holman, J. Keirns
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> ASP015K is an oral Janus kinase (JAK) inhibitor of JAK1/3 in development for treatment of autoimmune diseases (eg, psoriasis, rheumatoid arthritis). <h3>Objectives</h3> Pharmacokinetics (PK), safety, and tolerability of ASP015K were assessed in 2 double-blind, placebo-controlled, dose-escalation trials in healthy subjects. <h3>Methods</h3> Study A: single doses of ASP015K 3–300 mg or placebo (PBO) were given in 9 sequential groups (n=6 active: 2 PBO/group). Study B: 3 groups of men received ASP015K 30, 100, or 200 mg twice daily (BID) or PBO, and 1 group of women received 100 mg BID or PBO (n=9 active:3 PBO/group) for 13.5 days. Plasma PK parameters were calculated with noncompartmental methods. Adverse events (AEs), clinical labs, vital signs, and electrocardiograms (ECGs) were evaluated. <h3>Results</h3> After single doses under fasted conditions, ASP015K was rapidly absorbed with median time to maximum observed concentration (t<sub>max</sub>) ≤1.75 hours. Mean maximum observed concentration (C<sub>max</sub>) and area under the curve from time 0 extrapolated to infinity (AUC<sub>inf</sub>) increased dose proportionally. Elimination was multiphasic with terminal mean half-life (t<sub>1/2</sub>) of 7.0–13 hours at clinically relevant doses (≥60 mg). Food increased C<sub>max</sub> by 5% and AUC<sub>inf</sub> by 27% and delayed t<sub>max</sub> by ∼2.5 hours. After BID dosing in a fed state, exposure reached steady state on day 3, with C<sub>max</sub> and AUC<sub>12h</sub> increasing relatively dose proportionally. Mean accumulation factor (day 14 vs day 1) was 1.12–1.65 for C<sub>max</sub>, 1.38–1.65 for AUC<sub>12h</sub>, and 2.02–2.71 for C<sub>trough</sub>. There was no statistically significant sex difference in PK with single or multiple doses. There was no evidence of dose-limiting toxicities or significant safety findings with single doses. With multiple doses, 75% (27/36) of ASP015K subjects and 42% (5/12) of PBO subjects had AEs, mostly mild or moderate; no serious AEs occurred. The most common AEs were neutropenia, headache, and abdominal pain, with apparent dose dependency. Three subjects discontinued due to AEs (1 man with moderate vomiting [100 mg]; 1 man with mild-to-moderate neutropenia [200 mg BID]; 1 woman with severe neutropenia [100 mg BID]). There were no clinically significant changes in labs, vital signs, or ECG (no positive correlation between ASP015K concentration and QTcF). <h3>Conclusions</h3> ASP015K was generally well tolerated and showed rapid absorption with small food effect, elimination t<sub>1/2</sub> &gt;7 hours at clinically relevant doses, and modest accumulation after BID dosing. Plasma exposure was relatively dose proportional, with no significant sex differences in PK. <h3>Disclosure of Interest</h3> T. Zhu Employee of: Astellas Pharma Global Development, T. Sawamoto Employee of: Astellas Pharma, Inc., U. Valluri Employee of: Astellas Pharma Global Development, M. Lewand Employee of: Astellas Pharma Global Development, Y. Cao Employee of: Astellas Pharma Global Development, S. Swan: None Declared, K. Lasseter: None Declared, M. Matson: None Declared, J. Holman Employee of: Astellas Pharma Global Development, J. Keirns Employee of: Astellas Pharma Global Development