Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Saxagliptin

Background and Objective: Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for anti-hyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects. Methods: Two open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza (TM)). Results: Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(infinity)) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC(infinity) values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CL(CR)) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC(infinity) generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session. In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC(infinity) values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects. Conclusions: One-half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CL(CR) 30-50 mL/min) or severe (CL(CR) < 30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.