Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species.
Semaglutide is a human glucagon-like peptide-1 analogue in clinical development for the treatment of type 2 diabetes. The absorption, metabolism and excretion of a single 0.5mg/450μCi [16.7MBq] subcutaneous dose of [3H]-radiolabelled semaglutide was investigated in healthy human subjects and compared with data from nonclinical studies. Radioactivity in blood, plasma, urine and faeces was determined in humans, rats and monkeys; radioactivity in expired air was determined in humans and rats. Metabolites in plasma, urine and faeces were quantified following profiling and radiodetection. The blood-to-plasma ratio and pharmacokinetics of both radiolabelled semaglutide-related material and of semaglutide (in humans only) were assessed. Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69-83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys. The metabolite profiles of semaglutide in humans appear to be similar to the profiles from the nonclinical species investigated.
Novo Nordisk A/S, Søborg, Denmark. Electronic address: lejx@novonordisk.com.
Lene
L
Jensen
Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark. Electronic address: hhll@novonordisk.com.
Hans
H
Helleberg
PRA Health Sciences Early Development Services, Van Swietenlaan 6, 9728 NZ Groningen, The Netherlands. Electronic address: roffelad@prahs.com.
Ad
A
Roffel
PRA Health Sciences Early Development Services, Van Swietenlaan 6, 9728 NZ Groningen, The Netherlands. Electronic address: lierjanjaapvan@prahs.com.
Jan Jaap
JJ
van Lier
Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark. Electronic address: inbj@novonordisk.com.
Inga
I
Bjørnsdottir
Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark. Electronic address: pjcp@novonordisk.com.
Palle Jacob
PJ
Pedersen
Novo Nordisk Inc., Princeton, NJ, USA. Electronic address: evertondrowe@gmail.com.
Everton
E
Rowe
Novo Nordisk A/S, Søborg, Denmark. Electronic address: jdka@novonordisk.com.
Julie
J
Derving Karsbøl
Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark. Electronic address: mlup@novonordisk.com.
Mette Lund
ML
Pedersen
D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D005243:Feces; D004763:Glucagon-Like Peptides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium; D000099194:Semaglutide
D004763:Glucagon-Like Peptides; D014316:Tritium; D000099194:Semaglutide
AME; Clinical; GLP-1 analog; Metabolism; Nonclinical; Semaglutide