alx-0600 and Renal-Insufficiency

Teduglutide is a recombinant analogue of human glucagon-like peptide-2 that has recently been approved for the treatment of short bowel syndrome in adults. This study was designed to study the influence of renal function and age on teduglutide pharmacokinetics.. This was an open-label study with six parallel groups (6 subjects each). Three groups with renal impairment (moderate, severe and end-stage renal disease) were compared to healthy subjects with normal renal function, which were matched to the renal-impaired subjects with respect to demographics. At least two elderly subjects (≥65 years) were enrolled per group. A single dose of 10 mg teduglutide was subcutaneously administered to each subject. Teduglutide plasma concentrations were measured using a validated liquid chromatography method with tandem mass spectrometric detection, and the primary pharmacokinetic variables (AUCinf and Cmax) were calculated.. Area under the concentration versus time curve extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of teduglutide in subjects with end-stage renal disease were approximately 2.59- and 2.08-fold higher, respectively, than those of healthy subjects. The AUCinf and Cmax were also slightly higher in subjects with moderate and severe renal impairment. Comparison of healthy subjects aged <65 years with healthy elderly subjects revealed very similar pharmacokinetics in both subgroups.. In our study population, the primary pharmacokinetic parameters of teduglutide increased with increased severity of renal impairment. These results suggest that the daily dose of teduglutide should be reduced by 50 % in patients with moderate and severe renal impairment and end-stage disease. We found no effect of age on the pharmacokinetics of teduglutide in healthy subjects. The treatment was well tolerated, and there were no safety concerns.

Topics: Adolescent; Adult; Age Factors; Aged; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Renal Insufficiency

Teduglutide is a recombinant analogue of human glucagonlike peptide-2 (GLP-2) that was recently approved by the US and European regulatory agencies FDA and EMA for the treatment of short bowel syndrome (SBS). The objectives of this work were, firstly, to develop a population pharmacokinetic (popPK) model based on the available PK data of the entire clinical development program and, secondly, to utilize the model for the justification of the proposed dosing regimen. The exploratory analysis was based on a previously established structural PK model and focused primarily on the investigation of covariate effects.. The plasma concentrationtime profiles of teduglutide after subcutaneous application were adequately described by a 1-compartment model with first order absorption and elimination. The area under the curve (AUC) was lower for male subjects, for subjects with higher creatinine clearance, for overweight subjects, and for SBS patients. However, except for subjects with severe renal impairment no clinically relevant effects on AUC were identified.. Our model-based analysis supports the approved dose adjustment for SBS patients with and without renal impairments maintaining the exposure in a value range with acceptable variance for the target population.

Topics: Adolescent; Adult; Aged; Drug Approval; Drug Interactions; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Models, Biological; Peptides; Renal Insufficiency; Short Bowel Syndrome