A Randomized Trial Investigating the Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Semaglutide Once-Weekly in Healthy Male Japanese and Caucasian Subjects

Ippei Ikushima, Lene Jensen, Anne Flint, Tomoyuki Nishida, Jeppe Zacho, Shin Irie, Ippei Ikushima, Lene Jensen, Anne Flint, Tomoyuki Nishida, Jeppe Zacho, Shin Irie

Abstract

Introduction: Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects.

Methods: In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg (n = 8), 1.0 mg (n = 8), placebo 0.5 mg (n = 3) or 1.0 mg (n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC0-168h)].

Results: Steady-state exposure of semaglutide was similar for both populations: AUC0-168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration (Cmax) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC0-168h ERR 1.11; Cmax ERR 1.14). Dose-dependent increases in AUC0-168h and Cmax occurred in both populations. Accumulation was as expected, based on the half-life (t1/2, ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified.

Conclusions: The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects.

Funding: Novo Nordisk A/S, Denmark.

Trial registration: ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.

Keywords: GLP-1 receptor agonist; Japanese subjects; Pharmacodynamics; Pharmacokinetics; Semaglutide; Type 2 diabetes.

Figures

Fig. 1
Fig. 1
Study design. BMI body mass index, PD pharmacodynamic, PK pharmacokinetic, SD single dose, SS steady state
Fig. 2
Fig. 2
Mean semaglutide profile from first dosing to follow-up. Values are geometric means. From day 7 to day 84 all samples were taken immediately prior to next semaglutide dose (trough samples). All values below the lower limit of quantification are imputed
Fig. 3
Fig. 3
Mean semaglutide profile at steady state: 0–168 h after last dose. Values are geometric means

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