Dataset Information

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 (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUCinf) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized Cmax was 45.7-98.8% higher and AUCinf 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. Dose-proportional 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.

SUBMITTER: Shibata M

PROVIDER: S-EPMC7181426 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Shibata Mai M Hatta Toshifumi T Saito Masako M Toyoshima Junko J Kaneko Yuichiro Y Oda Kazuo K Nishimura Tetsuya T

Clinical drug investigation 20200501 5

<h4>Background and objective</h4>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.<h4>Methods</h4>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 peficitini ...[more]

PMID: 32274653

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Project description:BACKGROUND AND OBJECTIVE:Atacicept is an inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), and is being studied in relation to immunological disease. Currently, limited data on atacicept are available in non-Caucasian subjects. Pharmacokinetic data from earlier studies of atacicept were derived using an enzyme-linked immunosorbent assay (ELISA), which was subsequently found to have inadequacies. Hence, a new bioanalytical ELISA for total atacicept was developed and validated. We conducted this randomized, double-blind, placebo-controlled phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of atacicept in healthy Japanese and Caucasian subjects while generating pharmacokinetic data using the new ELISA. METHODS:Japanese subjects aged???18 to???55 years (n? =?24) were randomized (1:1:1:1) to a single subcutaneous dose of atacicept 25, 75, or 150 mg or placebo. Caucasian subjects were then enrolled to match the Japanese subjects' gender, body weight (±?20%), and height (±?15%). RESULTS:Atacicept was well tolerated and there were no clinically significant differences in treatment-emergent adverse events (TEAEs), vital signs, or laboratory parameters between the Japanese and Caucasian subjects. Most (90%) TEAEs were mild; no severe or serious TEAEs or deaths occurred. Weight-adjusted atacicept exposure was comparable between ethnicities and across doses: the Japanese/Caucasian ratio of the area under the serum concentration-time curve from time zero to the last sampling point (AUC0-t) was 107.21% (90% CI 93.42-123.02%) and the Japanese/Caucasian ratio of maximum serum concentration (Cmax) was 95.74% (90% CI 74.26-123.43%; ANCOVA). Median time to reach Cmax (tmax) was 20-60 h across all subjects. Dose-exposure relationships were comparable for the two ethnicities, with dose-normalized AUC0-t decreasing with increasing dose, indicating nonlinear pharmacokinetics for the doses examined. There were no statistically significant differences between ethnicities in the pharmacokinetics-dose relationship. Some transient dose-related decreases in mean serum immunoglobulin (Ig)A and IgM, but not IgG, were observed after atacicept administration. There were small transient increases in peripheral B cell numbers in the first 4 days after dosing that were larger with atacicept than with placebo, with no apparent dose relationship. No anti-atacicept antibodies were detected. CONCLUSION:The safety, pharmacokinetic, and pharmacodynamic profiles of atacicept in healthy Japanese subjects were comparable to those in healthy Caucasian subjects. EudraCT-ID: 2013-002703-34.

Project description:Background and objectivesRotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson's disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects.MethodsIn this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration-time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values).ResultsThe pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0±0.5 mg for Japanese subjects and 2.08±0.58 mg for Caucasians. Plasma concentration-time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine=unconjugated rotigotine+conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1% of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7% of absorbed dose in Japanese subjects and 10.8% of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1%, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5% in Japanese subjects and 4.2% Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics.ConclusionAdministration of a single patch delivering 2 mg/24 h rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.

Dataset Information

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

Publications

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

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