Endocrine Abstracts

Background/aims: Saxagliptin is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme. Saxagliptin is cleared by both metabolism and renal excretion. The aims of this study were to determine the effect of renal impairment (RI) and haemodialysis (HD) on the pharmacokinetics of saxagliptin.

Methods: This open-label, parallel-group study was conducted in subjects with normal renal function (glomerular filtration rate (GFR)>80 ml/min), mild (50–80 ml/min), moderate (30–50 ml/min) and severe (<30 ml/min) RI, and end-stage renal disease (ESRD) requiring HD (8 subjects/category) in clinical pharmacology units. Subjects were administered single oral doses of saxagliptin (10 mg), and on a separate occasion received intravenous iohexol for a secondary GFR assessment (not HD subjects). A 4-h HD session was started 2 h after saxagliptin dosing in ESRD subjects. Serial blood and cumulative urine samples for pharmacokinetic assessments of saxagliptin, its major active metabolite (BMS-510849), and iohexol were collected.

Results: Iohexol systemic clearance correlated well with estimated GFR. The degree of RI did not affect the C_max of saxagliptin or its major metabolite. In mild RI subjects, the overall mean systemic exposure (AUC_∞) values of saxagliptin and its major metabolite were 1.2- and 1.7-fold higher, respectively, than mean AUC_∞ values in subjects with normal renal function. The saxagliptin and metabolite AUC_∞ values in moderate RI subjects were 1.4- and 2.9-fold higher, respectively, than subjects with normal renal function. The corresponding values in severe RI subjects were 2.1- and 4.5-fold higher, respectively. A 4-h HD session removed 23% of the saxagliptin dose.

Conclusion: AUC_∞ values for saxagliptin and, to a greater extent, its major metabolite were correlated with the degree of RI, whereas C_max values were not well-correlated. Saxagliptin and its metabolite were cleared by haemodialysis.