Drug Res (Stuttg) 2019; 69(09): 479-486
DOI: 10.1055/a-0885-1429
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Pharmacokinetic Study of SKL-18287, a Novel Long-Acting Glucagon-Like Peptide-1 Receptor Agonist, in Rats, Monkeys and Mini-Pigs

Mitsuaki Takeuchi
1   Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
2   Licensing & Business Development, R&D Strategy Center, Sanwa Kagaku Kenkyusho Co., Ltd., Tokyo, Japan
,
Masayuki Okamoto
1   Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
,
Miyuki Tamura
1   Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
,
Takayo Murase
1   Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
,
Nobuhide Watanabe
1   Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
2   Licensing & Business Development, R&D Strategy Center, Sanwa Kagaku Kenkyusho Co., Ltd., Tokyo, Japan
› Author Affiliations
Further Information

Publication History

received 21 December 2018

accepted 26 March 2019

Publication Date:
13 May 2019 (online)

Abstract

Background Long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for treatment of type 2 diabetes (T2DM) in the United States, the European Union, and Japan. In our previous work, we designed and characterized a novel GLP-1 RA, SKL-18287. This RA consists of only natural L-amino acids, and is believed to exist in an oligomer form in systemic circulation. This unique feature may allow high biological stability and a long-lasting glucose lowering effect in T2DM treatment. In the present study, we investigated the pharmacokinetic properties of SKL-18287 in rats, monkeys, and mini-pigs. Tissue distributions of radioactivity were also studied in rats after subcutaneous administration of [3H]-SKL-18287.

Methods Plasma concentrations of SKL-18287 were measured by LC-MS/MS after intravenous and subcutaneous administration of SKL-18287 in rats, monkeys, and mini-pigs. Pharmacokinetic parameters were then calculated and compared among these animal species. Tissue concentrations of radioactivity were determined by liquid scintillation counting following sample combustion, after subcutaneous administration of [3H]-SKL-18287 to rats.

Results SKL-18287 showed an extended half-life of over 5 h, with good subcutaneous bioavailability, in all animal species. Prediction of the pharmacokinetic profiles of SKL-18287 in humans using an animal scale-up approach revealed an SKL-18287 half-life of 14.8 h. The radioactivity concentration in the pancreas, a target tissue of GLP-1RA, was relatively higher than in other tissues, until 12 h after [3H]-SKL-18287 administration.

Conclusion SKL-18287 might be sufficient to maintain an effective concentration for a once-daily treatment for T2DM, and is a unique GLP-1 RA with a pancreas-selective feature.

 
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