Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects
| Autor: | Susan E. Walker, Rebecca J. Hodge, Mark A. Bush, Robert L. Dobbins, Jessica E. Matthews, Murray Stewart, E. H. De Boever, M. Gutierrez, M. C. Holland |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Blood Glucose Male Endocrinology Diabetes and Metabolism Cmax Pharmacology Placebo Young Adult Endocrinology Pharmacokinetics Glucagon-Like Peptide 1 Internal Medicine Humans Medicine Glycated Hemoglobin Dose-Response Relationship Drug business.industry Area under the curve Middle Aged Albiglutide Treatment Outcome Tolerability Area Under Curve Pharmacodynamics Cohort Female business Half-Life |
| Zdroj: | Diabetes, Obesity and Metabolism. 11:498-505 |
| ISSN: | 1463-1326 1462-8902 |
| DOI: | 10.1111/j.1463-1326.2008.00992.x |
| Popis: | Aims: Albiglutide is a glucagon-like peptide-1 (GLP-1) mimetic generated by genetic fusion of a dipeptidyl peptidaseIV-resistant GLP-1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP-1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/ tolerability profile of albiglutide in non-diabetic volunteers. Methods: In this single-blind, randomized, placebo-controlled trial, 39 subjects (18–60 years, body mass index 19.9–35.0 kg/m 2 ) received placebo (n ¼ 10) or escalating doses of albiglutide (n ¼ 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 þ 1 mg; cohort 2: 3 þ 6 mg; cohort 3: 16 þ 24 mg; cohort 4: 48 þ 60 mg; and cohort 5: 80 þ 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC(0–7 days))] and maximum plasma drug concentration (Cmax) for cohorts 2–5 during week 1. Results: Albiglutide had a terminal elimination half-life (T1/2) of 6–8 days and time to maximum observed plasma drug concentration (Tmax) of 3–4 days. A greater-than-dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose-dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug-related AE, followed by constipation, flatulence and nausea. Conclusions: Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects. |
| Databáze: | OpenAIRE |
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