Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment

Abstract

BackgroundSemaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) as a tablet for oral administration. This trial (NCT02014259) investigated the pharmacokinetics, safety and tolerability of oral semaglutide in subjects with and without renal impairment.MethodsSubjects were categorised as having normal renal function (n = 24), mild (n = 12), moderate (n = 12) or severe (n = 12) renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (n = 11) and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days) in the fasting state, followed by 30 min fasting after dosing. Semaglutide plasma concentrations were measured during dosing and for up to 21 days after the last dose.ResultsSemaglutide exposure (area under the plasma concentration–time curve from time zero to 24 h after the tenth dose and maximum concentration after the tenth dose) did not vary in a consistent pattern across the renal function groups. Similarly, there was no apparent effect of renal impairment on the semaglutide half-life (geometric mean range 152–165 h). Except for one subject in the ESRD group, semaglutide was not detected in urine. Haemodialysis did not affect the pharmacokinetics of semaglutide. Adverse events were in line with those observed for other GLP-1 receptor agonists and no safety concerns were identified.ConclusionThere was no apparent effect of renal impairment or haemodialysis on the pharmacokinetics of oral semaglutide. Based on this trial, renal impairment should not affect dose recommendations for oral semaglutide.

Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial

“…24 Oral semaglutide is the first oral GLP-1 receptor agonist and, once available, might be preferred to injections by some patients. Like liraglutide and subcutaneous semaglutide, the pharmacokinetics of oral semaglutide are not substantially affected by renal impairment, 11,12,25 making it potentially suitable for patients with chronic kidney disease.…”

“…In people without diabetes, the pharmacokinetics of oral semaglutide were not affected by renal impairment. 12 However, the efficacy and safety profile of oral semaglutide in patients with diabetes and renal impairment is unknown. In this phase 3a trial (PIONEER 5), we compared the efficacy and safety of once-daily oral semaglutide with placebo, in addition to existing background medication, in patients with type 2 diabetes and moderate renal impairment (eGFR of 30-59 mL/min per 1•73 m 2 ).…”

Semaglutide as a promising antiobesity drug

“…Furthermore, pharmacodynamics, pharmacokinetics, and safety of once‐weekly sc semaglutide were similar between Caucasian and Japanese healthy individuals as shown in a randomized trial . Pharmacokinetics, safety, and tolerability of oral semaglutide have been found not to be altered in patients with various degrees of renal or hepatic impairment, thus suggesting that no dose adjustments are needed for oral semaglutide in relation to renal or hepatic function …”

“…Another meta‐analysis showed that semaglutide‐treated patients were less likely to develop nausea compared with the other GLP‐1 RAs . In terms of pharmacokinetics, no semaglutide dose adjustments are required in patients with renal or liver dysfunction or in patients receiving warfarin, digoxin, atorvastatin, or metformin …”

Shifting Paradigms Revisited: Biotechnology and the Pharmaceutical Sciences

“…The company expects to launch this oral formulation before mid 2019. 84,85 The Dermal Route Does the dermal route offer opportunities to deliver biologics for systemic use? Up until now, all attempts of transporting therapeutically relevant doses of proteins through the intact skin by using patch-type devices have failed.…”