PIII-60Effect of renal insufficiency on the pharmacokinetics of MK-0431 (sitagliptin), a selective dipeptidyl-peptidase-IV (DPP-IV) inhibitor

Abstract

BACKGROUND/AIMS This study was conducted to evaluate the influence of renal insufficiency (RI) on the pharmacokinetics (PK) of sitagliptin (SIT), a selective DPP-IV inhibitor in Phase III development for the treatment of type 2 diabetes. METHODS 6 patients/subjects in each of the following groups: mild RI (creatinine clearance (CrCl) = 50 to 80 mL/min), moderate RI (CrCl = 30 to 50 mL/min), severe RI (CrCl < 30 mL/min) and healthy subjects (CrCl > 80 mL/min). Each group received a single oral 50-mg dose of SIT. End-stage renal disease (ESRD) patients received 2 single oral 50-mg doses (hemodialysis 4-hr or 48-hr postdose). SIT PK in RI patients was compared to concurrent and historical control subjects. Less than 2-fold increases in AUC0-∞were not considered clinically meaningful changes. RESULTS SIT AUC0-∞ was approximately inversely related to CrCl. Renal clearance (ClR) was approximately proportional to CrCl. AUC0-∞ increased less than 2-fold for CrCl > 50 mL/min. AUC0-∞ was 1.6, 2.3, 3.8 and 4.5-fold higher in mild RI, moderate RI, severe RI and ESRD patients, respectively, compared to healthy subjects. Cmax was 1.4, 1.4, 1.8 and 1.4 higher in mild moderate and severe RI and ESRD, respectively. Dialysis removed ∼13.5% of the dose. SIT was well tolerated in all groups. CONCLUSIONS Mild RI patients do not require dose-adjustment. To obtain an exposure of SIT similar to patients without renal insufficiency, moderate RI, and severe RI and ESRD patients should receive ½ and ¼ of the usual SIT dose, respectively. Clinical Pharmacology & Therapeutics (2005) 79, P75–P75; doi: 10.1016/j.clpt.2005.12.268