Pharmacokinetics, Safety and Tolerability of Once-Weekly Subcutaneous Semaglutide in Healthy Chinese Subjects: A Double-Blind, Phase 1, Randomized Controlled Trial

Abstract

Introduction: Once-weekly (OW) subcutaneous (s.c.) semaglutide is an injectable glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. This trial was designed to assess the pharmacokinetics, safety and tolerability of OW s.c. semaglutide in healthy Chinese subjects.

Methods: In this single-centre, randomised, double-blind, placebo-controlled trial, 36 healthy subjects were randomised to OW s.c. semaglutide 0.5 mg (n = 12), 1.0 mg (n = 12), or placebo (n = 12). Treatment (semaglutide or placebo) was blinded for the subjects, investigators and sponsor. The primary endpoint was steady-state semaglutide exposure, defined as the area under the curve over a dosing interval at steady state (AUC_{0-168 h,SS}).

Results: In total, 34 subjects completed the trial. The steady-state exposure of semaglutide was higher for subjects treated with 1.0 mg semaglutide (AUC_{0-168 h,ss}: 7961 nmol h/l and C_max,ss: 55.9 nmol/l) compared to 0.5 mg semaglutide (AUC_{0-168 h,ss}: 4000 nmol h/l and C_max,ss: 28.8 nmol/l). The total exposure of semaglutide increased in a dose-proportional manner in healthy Chinese subjects; the treatment ratio (1.0 mg/0.5 mg) [95% confidence interval] for AUC_{0-168 h,SS} was 1.99 [1.78; 2.23]. Treatment with OW s.c. semaglutide was well tolerated in healthy Chinese subjects. As expected for the GLP-1 receptor agonist class, the most common adverse events were gastrointestinal, and no new safety signals were identified.

Conclusion: The pharmacokinetics, safety and tolerability of OW s.c. semaglutide in healthy Chinese subjects were consistent with previous clinical pharmacology trials of OW s.c. semaglutide in other populations. The results suggest that no dose adjustment is necessary for semaglutide in Chinese patients with T2D.

Trial registration: ClinicalTrials.gov, identifier NCT03288740.

Keywords: Diabetes; Glucagon-like peptide-1 receptor agonist; Pharmacokinetics; Randomised controlled trial; Semaglutide; Steady state exposure.

Fig. 1

Trial design. Subjects in blue treatment groups were treated with OW s.c. semaglutide; subjects in grey treatment groups were dosed with corresponding volume of placebo. PK pharmacokinetics, OW once weekly, s.c. subcutaneous

Fig. 2

Flow diagram of subjects. ^aOne subject withdrew from the trial, one subject was withdrawn because of violation of a dosing day exclusion criterion (‘use of prescription or non-prescription systemic products or topical medicinal products within 3 weeks prior to the visit’) and four subjects were withdrawn because of adverse events. ^bVolume-matched placebo (six subjects on placebo 0.5 mg; six subjects on placebo 1.0 mg). ^cSubject was withdrawn owing to violation of a dosing day exclusion criterion before the final dose. ^dSubject was withdrawn owing to an SAE unrelated to treatment (traffic accident) after receiving all planned doses of trial product. OW once weekly, SAE serious adverse event, s.c. subcutaneous

Fig. 3

Geometric mean semaglutide concentration over time for a the full trial duration and b over a dosing interval at steady state. The dashed lines denote the lower limit of quantification. Values below this limit were imputed. Sema semaglutide

Fig. 4

a Average observed semaglutide concentration and b body weight- and dose-normalised average semaglutide concentration across clinical pharmacology trials of OW s.c. semaglutide. Study 1 was conducted in Japan and included healthy Japanese and Caucasian subjects [23]; study 2 was conducted in the UK and included subjects with obesity [29]; studies 3 and 4 were conducted in Germany and included healthy subjects [28]. C_avg was calculated as AUC_0–168 h/168 h. Weight- and dose-normalised exposure for each individual subject was calculated as: C_avg/(dose × body weight^0.988). Error bars represent 90% ranges for the C_avg