title: Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administrations in healthy subjects.
abstract: Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50-mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.
authors.affiliation: Pharsight Corporation, Montreal, QC, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Marier
authors.forename: Martin
authors.initials: M
authors.lastname: Beliveau
authors.forename: Mohamad-Samer
authors.initials: MS
authors.lastname: Mouksassi
authors.forename: Paula
authors.initials: P
authors.lastname: Shaw
authors.forename: Jane
authors.initials: J
authors.lastname: Cyran
authors.forename: Jothi
authors.initials: J
authors.lastname: Kesavan
authors.forename: John
authors.initials: J
authors.lastname: Wallens
authors.forename: Hamim
authors.initials: H
authors.lastname: Zahir
authors.forename: David
authors.initials: D
authors.lastname: Wells
authors.forename: John
authors.initials: J
authors.lastname: Caminis
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D053767:Glucagon-Like Peptide 2 / Q000737:chemistry*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D053767:Glucagon-Like Peptide 2; D010455:Peptides; C494910:teduglutide