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AB0364 Pharmacokinetics, safety, and tolerability of asp015k, a novel janus kinase inhibitor, in healthy volunteers
  1. T. Zhu1,
  2. T. Sawamoto2,
  3. U. Valluri1,
  4. M. Lewand1,
  5. Y. Cao1,
  6. S. Swan3,
  7. K. Lasseter4,
  8. M. Matson5,
  9. J. Holman1,
  10. J. Keirns1
  1. 1Astellas Pharma Global Development, Northbrook, United States
  2. 2Astellas Pharma, Inc., Tokyo, Japan
  3. 3DaVita Clinical Research, Minneapolis
  4. 4Clinical Pharmacology of Miami, Miami
  5. 5Prism Research, St Paul, United States

Abstract

Background ASP015K is an oral Janus kinase (JAK) inhibitor of JAK1/3 in development for treatment of autoimmune diseases (eg, psoriasis, rheumatoid arthritis).

Objectives Pharmacokinetics (PK), safety, and tolerability of ASP015K were assessed in 2 double-blind, placebo-controlled, dose-escalation trials in healthy subjects.

Methods 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.

Results After single doses under fasted conditions, ASP015K was rapidly absorbed with median time to maximum observed concentration (tmax) ≤1.75 hours. Mean maximum observed concentration (Cmax) and area under the curve from time 0 extrapolated to infinity (AUCinf) increased dose proportionally. Elimination was multiphasic with terminal mean half-life (t1/2) of 7.0–13 hours at clinically relevant doses (≥60 mg). Food increased Cmax by 5% and AUCinf by 27% and delayed tmax by ∼2.5 hours. After BID dosing in a fed state, exposure reached steady state on day 3, with Cmax and AUC12h increasing relatively dose proportionally. Mean accumulation factor (day 14 vs day 1) was 1.12–1.65 for Cmax, 1.38–1.65 for AUC12h, and 2.02–2.71 for Ctrough. 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).

Conclusions ASP015K was generally well tolerated and showed rapid absorption with small food effect, elimination t1/2 >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.

Disclosure of Interest 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

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