Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects

Cao, Ying; Sawamoto, Taiji; Valluri, Udaya; Cho, Kathy; Lewand, Michaelene; Swan, Suzanne K.; Lasseter, Kenneth C.; Matson, Mark; Holman, John; Keirns, James J.; Zhu, Tong

doi:10.1002/cpdd.273

Cited by 25 publications

(64 citation statements)

References 15 publications

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“…The studies, which evaluated single (3-300 mg) and multiple (30-200 mg twice daily) peficitinib oral dosing in healthy predominantly Caucasian subjects, demonstrated rapid absorption at all doses, and the attainment of steady-state plasma levels by day 3 of multiple twice-daily dosing. The plasma concentration of peficitinib increased proportionally with increasing single and multiple doses, and no significant differences in the pharmacokinetics and pharmacodynamics of peficitinib were observed between the sexes [11].…”

Section: Sample Sizementioning

confidence: 90%

“…This was a single-center, randomized, double-blind, placebo-controlled study to assess the pharmacokinetics, (six receiving peficitinib and two receiving placebo per dose level). The sample size was based on practical considerations and on the sample sizes in the US single-and multipledose pharmacokinetic/pharmacodynamic studies [11].…”

Section: Methodsmentioning

confidence: 99%

“…The pharmacokinetics and pharmacodynamics of peficitinib have been characterized in two phase 1, randomized, placebo-controlled, escalating-dose studies conducted in the USA [11]. The studies, which evaluated single (3-300 mg) and multiple (30-200 mg twice daily) peficitinib oral dosing in healthy predominantly Caucasian subjects, demonstrated rapid absorption at all doses, and the attainment of steady-state plasma levels by day 3 of multiple twice-daily dosing.…”

Section: Sample Sizementioning

confidence: 99%

“…Signal transducer and activator of transcription 5 (STAT5) phosphorylation activity (used as a biomarker for JAK enzyme activity [11,19]) and lymphocyte subsets were assessed (see Supplementary Table S1). STAT5 phosphorylation was quantified using the difference in mean fluorescence intensity from flow cytometric analysis of CD3positive lymphocytes stained with anti-phosphorylated STAT5 antibodies, with and without IL-2 stimulation.…”

Section: Pharmacodynamic Assessmentsmentioning

confidence: 99%

“…Neither STAT5 phosphorylation nor lymphocyte subset had an upper or lower limit of quantitation. Percentage of STAT5 phosphorylation inhibition (i.e., JAK inhibition) was calculated as reported in a previous study [11].…”

Section: Pharmacodynamic Assessmentsmentioning

confidence: 99%

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Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects

et al. 2020

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Background and Objective Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects. Methods In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) received peficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout. Results Dose proportionality of maximum plasma drug concentration (C max ) and area under the plasma concentration-time curve extrapolated to infinity (AUC inf ) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized C max was 45.7-98.8% higher and AUC inf was 33.8-66.4% higher in Japanese versus Caucasian subjects. Mean peak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation. Conclusions Peficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Doseproportional exposure was demonstrated across the single-dose range of 20-200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations. ClinicalTrials.gov identifier NCT01225224.

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Section: Sample Sizementioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Sample Sizementioning

confidence: 99%

Section: Pharmacodynamic Assessmentsmentioning

confidence: 99%

Section: Pharmacodynamic Assessmentsmentioning

confidence: 99%

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Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects

et al. 2020

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JAK Family Inhibitors for Autoimmune Diseases

Borzilleri

Hart

Moslin

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The JAK family of non‐receptor tyrosine kinases mediates the signaling of proinflammatory cytokines that contribute to the pathogenesis of numerous autoimmune diseases. While cytokine‐directed therapies are available to treat immune‐driven diseases, oral small‐molecule inhibitors of the JAK family (Jakinibs) have been approved as viable alternatives for the treatment of RA, PsA, and IBD. These first‐generation pan‐JAK inhibitors target the highly conserved catalytically active kinase domains in a reversible, ATP‐competitive manner, albeit in a nonselective fashion. Novel approaches to target alternative binding modes through, for example irreversible or allosteric kinase inhibition, have led to the identification of the next generation of agents, which demonstrate improved JAK family selectivity. This improved selectivity offers the potential for greater and perhaps broader efficacy by allowing for higher dosing, while avoiding undesired side effects. This article provides an overview of the JAK‐STAT signaling pathway and outlines the challenges associated with the discovery of selective JAK inhibitors while highlighting a unique allosteric TYK2 inhibitor. For each of the agents discussed, a synopsis of the medicinal chemistry efforts leading to a particular molecule is provided along with a brief summary of available preclinical and clinical efficacy and safety data.

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Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function

Miyatake

Shibata

Toyoshima

et al. 2019

Clinical Pharm in Drug Dev

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Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUC inf) and maximum observed concentration (C max) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUC inf and C max , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

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Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects

Cited by 25 publications

References 15 publications

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects

JAK Family Inhibitors for Autoimmune Diseases

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function

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