Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment

Abstract

Semaglutide is a human glucagon-like peptide-1 analog that has been co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child-Pugh criteria, and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post-last dose. Area under the semaglutide plasma concentration-time curve from 0-24 hours after the 10th dose (primary end point) and maximum semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum semaglutide concentration (median range 1.0-1.5 hours) or half-life (geometric mean range 142-156 hours). No safety concerns were identified in subjects with hepatic impairment receiving semaglutide. Reported adverse events were in line with those observed for other glucagon-like peptide-1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral semaglutide. The results of this trial suggest that dose adjustment of oral semaglutide is not warranted in subjects with hepatic impairment.

Keywords: GLP-1 receptor agonists; hepatic impairment; pharmacokinetics; semaglutide.

Figure 1

Trial design. PK, pharmacokinetics.

Figure 2

Geometric mean concentration–time profiles of semaglutide after the 10th dose, by hepatic function group. Full analysis set.

Figure 3

AUC_{0–24h,Day10} and C_max,Day10 for semaglutide after the 10th dose, by hepatic function group. Full analysis set. Bars are estimated means and 95%CI. Treatment comparisons show estimated treatment ratio and 90%CI. AUC, area under the semaglutide plasma concentration–time curve; CI, confidence interval; C_max, maximum semaglutide concentration.

Figure 4

Mean concentration–time profiles of SNAC after the 10th dose, by hepatic function group. Full analysis set. SNAC, sodium N‐(8‐[2‐hydroxybenzoyl] amino) caprylate.

Figure 5

AUC_{0–24h,Day10} and C_max,Day10 for SNAC after the 10th dose, by hepatic function group. Full analysis set. Bars are estimated means and 95%CI. Treatment comparisons show estimated treatment ratio and 90%CI. AUC, area under the plasma concentration–time curve; CI, confidence interval; C_max, maximum concentration; SNAC, sodium N‐(8‐[2‐hydroxybenzoyl] amino) caprylate.