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Pharmacokinetics, Safety, and Tolerability of Teduglutide, a Glucagon-Like Peptide-2 (GLP-2) Analog, Following Multiple Ascending Subcutaneous Administrations in Healthy Subjects

From Pharsight Corporation, Montreal, QC, Canada (Dr Marier, Dr Beliveau, Dr Mouksassi); Northwest Kinetics Ltd, Tacoma, Washington (Dr Shaw); and NPS Pharmaceuticals, Inc, Parsippany, New Jersey (Dr Cyran, Dr Kesavan, Mr Wallens, Dr Zahir, Dr Wells, Dr Caminis). Dr Zahir is currently at Daiichi-Sankyo, Edison, New Jersey. Dr Wells is currently at Concert Pharmaceuticals, Lexington, Massachusetts. Dr Caminis is currently at Eurand Pharmaceuticals, Yardley, Pennsylvania.

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.

Key Words: Teduglutide • multiple-ascending dose • subcutaneous • pharmacokinetics • safety and tolerability

Address for reprints: John L. Wallens, MBA, Director, Clinical Operations, NPS Pharmaceuticals, Bedminster, New Jersey; e-mail: jwallens{at}npsp.com.

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