Semaglutide, 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.
Subjects 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.
Semaglutide 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.
There 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.
Arnouts P, Bolignano D, Nistor I, et al. Glucose-lowering drugs in patients with chronic kidney disease: a narrative review on pharmacokinetic properties. Nephrol Dial Transpl. 2014;29(7):1284–300. CrossRef
Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharmacol. 2015;55(5):497–504. CrossRef
Lau J, Bloch P, Schäffer L, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370–80. CrossRef
Sorli C, Harashima SI, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251–60. CrossRef
Ahrén B, Masmiquel L, Kumar H, et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5(5):341–54. CrossRef
Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(5):355–66. CrossRef
Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care. 2018;41(2):258–66. CrossRef
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. CrossRef
Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Crit Rev Ther Drug Carrier Syst. 2003;20(2–3):153–214. CrossRef
Graaf CD, Donnelly D, Wootten D, et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes. Pharmacol Rev. 2016;68(4):954–1013. CrossRef
Buckley ST, Schéele SG, Kirk RK, Knudsen LB. Mechanism of absorption mediated by SNAC in an oral formulation of semaglutide [poster]. Diabetes. 2017;66(Suppl 1):1206-P.
Connor A, Borregaard J, Buckley ST, et al. Site of absorption of an oral formulation of semaglutide [poster]. Diabetes. 2017;66(Suppl 1):1180-P.
Davies M, Pieber TR, Hartoft-Nielsen M-L, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017;318(15):1460–70. CrossRef
Marbury TC, Flint A, Jacobsen JB, Derving Karsbøl J, Lasseter K. Pharmacokinetics and tolerability of a single dose of semaglutide, a human glucagon-like peptide-1 analog, in subjects with and without renal impairment. Clin Pharmacokinet. 2017;56(11):1381–90. CrossRef
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. CrossRef
DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17:863–71. CrossRef
European Medicines Agency. Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function. 2004. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003123.pdf. Accessed Nov 2017.
US Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for industry. Pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling, Draft Guidance. 2010. Revision 1. https://www.fda.gov/downloads/drugs/guidances/ucm204959.pdf. Accessed Nov 2017.
Bækdal TA, Blicher TM, Donsmark M, Søndergaard FL. Safety, tolerability, and pharmacokinetics of single escalating doses of oral semaglutide in healthy male subjects [poster]. Diabetes. 2017;66(Suppl 1):1191-P.
Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70. CrossRef
Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384–95. CrossRef
Jacobsen LV, Hindsberger C, Robson R, Zdravkovic M. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol. 2009;68(6):898–905. CrossRef
Davidson JA, Brett J, Falahati A, Scott D. Mild renal impairment and the efficacy and safety of liraglutide. Endocr Pract. 2011;17(3):345–55. CrossRef
Loghin C, de la Peña A, Cui X, Zhang X, Geiser JS, Chien JY. Pharmacokinetics of once weekly dulaglutide in special populations [abstract no. 857]. Diabetologia. 2014;57(Suppl 1):S349.
Young MA, Wald JA, Matthews JE, Yang F, Reinhardt RR. Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide. Postgrad Med. 2014;126(3):35–46. CrossRef
Hanefeld M, Arteaga JM, Leiter LA, et al. Efficacy and safety of lixisenatide in patients with type 2 diabetes and renal impairment. Diabetes Obes Metab. 2017;19(11):1594–601. CrossRef
Jensen L, Helleberg H, Roffel A, et al. Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species. Eur J Pharm Sci. 2017;104:31–41. CrossRef
Osonoi T, Saito M, Tamasawa A, et al. Effect of hemodialysis on plasma glucose profile and plasma level of liraglutide in patients with type 2 diabetes mellitus and end-stage renal disease: a pilot study. PLoS One. 2014;9(12):e113468. CrossRef
Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203–16. CrossRef
Leiter LA, Carr MC, Stewart M, et al. Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study. Diabetes Care. 2014;37(10):2723–30. CrossRef
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA, LEADER Steering Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated with liraglutide: results from the LEADER randomized trial. Diabetes Care. 2017;40(7):966–72. CrossRef
- Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment
Flemming L. Søndergaard
Thomas W. Anderson
- Springer International Publishing