Pharmacokinetics and Tolerability of Semaglutide in Subjects with Hepatic Impairment

Presentation Number: SUN 621
Date of Presentation: April 2nd, 2017

Lene Jensen*1, Viera Kupcova2, Gerhard Arold3, Trine Kvist1, Jonas Pettersson1 and Julie Bousgaard Hjerpsted1
1Novo Nordisk A/S, Søborg, Denmark, 2Dérer´s Hospital, Bratislava, Slovakia, 3PRA Health Sciences, Berlin, Germany

Abstract

Background

Semaglutide is a glucagon-like peptide-1 receptor agonist in development for the treatment of type 2 diabetes. Impaired hepatic function may affect the pharmacokinetics (PK) of drugs. This trial investigated whether the PK of semaglutide was altered in subjects with various degrees of hepatic impairment (HI), versus subjects with normal hepatic function.

Methods

This was a multicenter, open-label, parallel-group trial in which subjects with varying degrees of HI or normal hepatic function received a single, subcutaneous dose of 0.5 mg semaglutide. Using the Child-Pugh criteria, (1) subjects with stable HI were assigned to one of three HI function groups (mild, moderate, or severe). Subjects with normal hepatic function were enrolled for comparison. Semaglutide plasma concentrations were assessed regularly up to 35 days (840 hours) post-dose. The primary PK endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-). ‘No effect’ was declared if the 90% confidence interval [CI] for the ratio between two groups was within the interval 0.70–1.43. Secondary endpoints included semaglutide maximum plasma concentration (Cmax), time to Cmax (tmax), terminal elimination half-life (t1/2), and protein binding (in vitro assessments on pre-dose plasma samples). The safety and tolerability of semaglutide was also assessed.

Results

Forty-four subjects were allocated to four HI function groups: normal (n=19), mild (n=8), moderate (n=10), and severe (n=7). Semaglutide exposure was similar across all groups as the AUC0- met the criterion of ‘no effect’ for all three HI groups versus the group with normal hepatic function (AUC0- treatment ratios [TRs] for mild/normal 0.95 [90% CI 0.77–1.16]; moderate/normal 1.02 [0.93–1.12]; severe/normal 0.97 [0.84–1.12]). In addition, semaglutide Cmax did not appear to be influenced by hepatic function, as TRs were mild/normal 0.99 [0.80–1.23], moderate/normal 1.02 [0.88–1.18] and severe/normal 1.15 [0.89–1.48] (sensitivity analysis excluding one extreme semaglutide concentration for one subject: 1.05 [0.88–1.25]). Median tmax and t1/2were similar (54–78 hours and 150–163 hours, respectively) in all groups. Plasma protein binding was >99% in all subjects. A total of 12 adverse events were reported in 10 subjects: none were serious and all were mild or moderate. No new safety or tolerability issues were observed.

Conclusion

Semaglutide exposure was not affected by hepatic impairment. Semaglutide was well tolerated and there were no new safety issues. The results suggest that no dose adjustment of semaglutide is necessary in subjects with HI.

 

Disclosure: LJ: Employee, Novo Nordisk, Employee, Novo Nordisk. TK: Employee, Novo Nordisk. JP: Employee, Novo Nordisk. JBH: Employee, Novo Nordisk. Nothing to Disclose: VK, GA