Clinical Pharmacokinetics

, Volume 50, Issue 4, pp 253–265

Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Saxagliptin

  • David Boulton
  • Li Li
  • Ernst U. Frevert
  • Angela Tang
  • Lorna Castaneda
  • Nimish N. Vachharajani
  • David M. Kornhauser
  • Chirag G. Patel
Original Research Article

DOI: 10.2165/11584350-000000000-00000

Cite this article as:
Boulton, D., Li, L., Frevert, E.U. et al. Clin Pharmacokinet (2011) 50: 253. doi:10.2165/11584350-000000000-00000

Abstract

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™).

Results

Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC 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 (CLCR) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC 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 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 5mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30–50 mL/min) or severe (CLCR <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.

Supplementary material

40262_2012_50040253_MOESM1_ESM.pdf (253 kb)
Supplementary material, approximately 259 KB.

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • David Boulton
    • 1
  • Li Li
    • 1
  • Ernst U. Frevert
    • 1
  • Angela Tang
    • 1
  • Lorna Castaneda
    • 1
  • Nimish N. Vachharajani
    • 1
  • David M. Kornhauser
    • 1
  • Chirag G. Patel
    • 1
  1. 1.Bristol-Myers SquibbPrincetonUSA
  2. 2.Discovery Medicine and Clinical PharmacologyBristol-Myers Squibb Research and DevelopmentPrincetonUSA