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Adv Drug Deliv Rev. 2018 May;130:113-130. doi: 10.1016/j.addr.2018.07.009. Epub 2018 Jul 21.

Battle of GLP-1 delivery technologies.

Author information

1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America.
2
Amneal Pharmaceuticals, 50 Horseblock Rd, Brookhaven, NY 11719, United States of America.
3
Siberian Federal University, 79 Svobodnuy Ave, Krasnoyarsk 660041, Russian Federation; Institute of Biophysics SBRAS, 50 Akademgorodok, 660036, Russian Federation.
4
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America; Biointerfaces Institute, NCRC, 2800 Plymouth Rd, Ann Arbor, MI 48109, United States of America; Department of Biomedical Engineering, 2200 Bonisteel Blvd, Ann Arbor, MI 48109, United States of America. Electronic address: schwende@umich.edu.
5
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109, United States of America; Biointerfaces Institute, NCRC, 2800 Plymouth Rd, Ann Arbor, MI 48109, United States of America. Electronic address: annaschw@med.umich.edu.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.

KEYWORDS:

Albumin fusion; Exenatide; Fatty acid conjugate; Fc fusion; GLP-1 receptor agonist; Half-life; Peptide delivery; Pharmacokinetics

PMID:
30009885
DOI:
10.1016/j.addr.2018.07.009

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