title: GSK2374697, a novel albumin-binding domain antibody (AlbudAb), extends systemic exposure of exendin-4: first study in humans--PK/PD and safety.
abstract: GSK2374697 is a genetically engineered fusion protein of a human domain antibody to exendin-4. This molecule binds with a high affinity to human serum albumin, creating a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist. This study is the first evaluation of the albumin-binding domain antibody (AlbudAb) drug delivery platform in humans. The aim of this randomized clinical study was to determine the pharmacokinetics, pharmacodynamics, safety, and tolerability of GSK2374697. The pharmacokinetic profile was prolonged, with estimated half-lives ranging from 6 to 10 days. Postprandial glucose and insulin were reduced, and gastric emptying was delayed in healthy subjects, confirming anticipated GLP-1 receptor agonist pharmacology. The safety and tolerability were as expected for a potent GLP-1 agonist. Gradual titration of doses greatly improved tolerability. Rapid tolerance to nausea was observed. Study results support further investigation in type 2 diabetes and for weight loss.
authors.affiliation: GlaxoSmithKline, R&D, Research Triangle Park, North Carolina, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: O'Connor-Semmes
authors.affiliation: GlaxoSmithKline, R&D, Research Triangle Park, North Carolina, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: GlaxoSmithKline, R&D, Research Triangle Park, North Carolina, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hodge
authors.affiliation: GlaxoSmithKline, R&D, Research Triangle Park, North Carolina, USA.
authors.forename: S
authors.initials: S
authors.lastname: Andrews
authors.affiliation: GlaxoSmithKline, R&D, Research Triangle Park, North Carolina, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chism
authors.affiliation: GlaxoSmithKline, R&D, King of Prussia, Pennsylvania, USA.
authors.forename: A
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: GlaxoSmithKline, R&D, Research Triangle Park, North Carolina, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Nunez
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000378:metabolism*; D001786:Blood Glucose / Q000032:analysis; D000077270:Exenatide; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010455:Peptides / Q000493:pharmacokinetics*; D011485:Protein Binding; D018027:Receptors, Glucagon / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D012709:Serum Albumin / Q000378:metabolism*; D014688:Venoms / Q000493:pharmacokinetics*
chemical_list: D000906:Antibodies; D001786:Blood Glucose; C000593833:GLP1R protein, human; C000594852:GSK2374697; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D014688:Venoms; D000082:Acetaminophen; D000077270:Exenatide