16th United European Gastroenterology Week
18 - 22 October 2008 · ACV · Vienna · Austria

Scientific Programme & EACCME

« back

OP234

PHARMACOKINETIC/PHARMACODYNAMIC CORRELATION BETWEEN TEDUGLUTIDE, AN ANALOG OF GLP-2, AND CITRULLINE, A BIOMARKER OF SMALL INTESTINAL ENTEROCYTE FUNCTIONAL MASS IN SHORT BOWEL PATIENTS

B. Messing*¹, S. Mouksassi², P. Jeppesen³, F. Joly⁴, L. Demchyshyn⁵, J. Cyran⁵, J. Marier²

¹Dept. of Gastroenterology, Hopital Beaujon, Clichy la Garenne, France, ², Pharsight Corp., Montreal, Canada, ³, Rigshospitalet, Copenhagen, Denmark, ⁴, Hopital Beaujon, Clichy, France, ⁵, NPS Pharmaceuticals, Bedminster, United States

Topics: 3.1 Enterocyte biology/pathology and nutrient/water transport/electrolyte transport

INTRODUCTION: Teduglutide is an analog of native human GLP-2, a naturally occurring peptide secreted in the intestine. With enhanced biological properties, teduglutide increases mucosal mass by increasing villus height and crypt depth. Teduglutide is currently under evaluation as a candidate for the treatment of intestinal dysfunction such as short bowel syndrome (SBS). The following study assessed the pharmacokinetic and pharmacodynamic (PK/PD) correlation between teduglutide and citrulline, an endogenous non-peptide amino acid that is a marker of small intestinal enterocyte mass, using PK/PD modelling techniques.

AIMS & METHODS: Eighty four PN-dependent SBS patients were randomized to placebo, 0.05 or 0.1 mg/kg/day of teduglutide for a 24-week treatment with follow-up of 4 weeks post-treatment. Teduglutide and citrulline plasma concentrations were determined every 4 weeks. PK/PD correlations were evaluated using an Emax model, with the maximum effect on citrulline driven by the cumulative exposure and duration of treatment with teduglutide.

RESULTS: As compared to baseline, mean citrulline levels at Week 24 following placebo, 0.05 and 0.10 mg/kg/day teduglutide increased by 7.9%, 49.4% and 113.1% with p-values of 0.1297, 0.001, and 0.001, respectively (Table).In the Emax model, the maximum predicted effect of teduglutide was a 142% increase in citrulline compared to baseline. The exposure of teduglutide associated with 50% of the maximum effect was 20 ng/mL. TABLE 1: Citrulline level as % of normal value (33 mu mol/L) PlaceboTG 0.05TG 0.1Week 067%54.6%50.4%Week 2473%89.7%97.5%

CONCLUSION: A PK/PD correlation was observed between cumulative exposure of teduglutide as demonstrated in the Emax model and significant increases in plasma citrulline as noted at week 24. These results suggest that citrulline may be a useful tool to assess changes in enterocyte mass in SBS patients treated with teduglutide.