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

Abstract

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.

Pharmacokinetics and Safety of Single and Multiple Doses of Peficitinib (ASP015K) in Healthy Chinese Subjects

“…The pharmacokinetic (PK) profiles of peficitinib and its key plasma metabolites (H1, H2 and H4, shown to have very weak pharmacological activity in a cell-based assay of T-cell proliferation) 13 , 18 have been examined extensively under fasted and fed conditions (for single- and multiple-dose administration, respectively), in two phase I randomized, placebo-controlled studies in the US 19 and a phase I randomized, placebo-controlled study in Japan; with significant differences in plasma concentrations observed between subjects of different ethnicities. 16 , 17 In the latter study, C max was 45.7–98.8% higher and AUC inf was 33.8–66.4% higher in Japanese versus Caucasian subjects. 16 Additionally, peficitinib was well tolerated and dose-proportional exposure was demonstrated in each study.…”

“… 12 Peficitinib has been approved for the treatment of patients with RA in Japan (2019) and Taiwan (2020). 13–15 It has also demonstrated rapid dose-proportional absorption after single- and multiple-dose administration; 16 however, absorption is delayed by a food effect following a moderate- to high-fat meal. 17 …”

Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis

“…As the RA patient model was constructed using PK data from an Asian population, the clinical relevance in other populations is currently unclear and caution should be used when applying this model to non‐Asian patients. The greater peficitinib exposure was observed in healthy Japanese compared with Caucasian with unknown reason 14 …”

“…These studies showed that peficitinib was absorbed rapidly, as demonstrated by time to maximum observed concentration (T max ) of 1.0–1.8 hours, and that food intake increased the area under the plasma concentration–time curve (AUC inf ) by 27–36% 12,13 . The mean terminal half‐life (t 1/2 ) of peficitinib ranged from 2.8 to 12.9 hours, 12 and dose‐proportional exposure was demonstrated within the dose ranges studied across single doses (3–300 mg) 12,14 . In addition, urinary excretion of peficitinib accounted for 9–15% of the oral dose, and 3 conjugated metabolites were found in plasma and urine (H2: sulfated; H4: methylated; H1: sulfated and methylated) 12,15 …”

“…12,13 The mean terminal half-life (t 1/2 ) of peficitinib ranged from 2.8 to 12.9 hours, 12 and dose-proportional exposure was demonstrated within the dose ranges studied across single doses (3-300 mg). 12,14 In addition, urinary excretion of peficitinib accounted for 9-15% of the oral dose, and 3 conjugated metabolites were found in plasma and urine (H2: sulfated; H4: methylated; H1: sulfated and methylated). 12,15 As part of phase 2 and phase 3 studies, data regarding the plasma concentrations of peficitinib in patients with RA were also collected.…”