Two randomized, double-blind, placebo-controlled studies are reported that had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus kinase (JAK) inhibitor, in healthy subjects. The single-dose study included 7 male groups (3-300 mg) and 2 female groups (30 or 200 mg), n = 8/group (6 on ASP015K and 2 on placebo in each group). The multiple-dose study included 1 female and 3 male groups, n = 12/group (9 on ASP015K and 3 on placebo in each group), who received ASP015K (30 mg) or placebo every 12 hours (twice a day) for 14 days. In the single-dose study, plasma ASP015K concentration increased dose-proportionally. Food increased ASP015K exposure (AUC ) by 27%. Mean peak JAK inhibition increased with dose, from 6% at 4 hours (median) following ASP015K 3 mg to 93% (range, 89%-98%) at 2 hours (median) after ASP015K 300 mg. In the multiple-dose study, ASP015K plasma exposure reached steady state by day 3. On day 14, mean ASP015K peak concentration was 38%-65% higher than after the first dose; peak JAK inhibition following 100 or 200 mg twice daily was >85%. The most common adverse events (AEs) were neutropenia, headache, and abdominal pain; no serious AEs occurred. The safety findings at pharmacologically effective doses of ASP015K support further clinical development.

Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.

IntroductionAmenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.MethodsThese studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.ResultsIn the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated.ConclusionThe findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearanceFundingAstellas Pharma.

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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 G...