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.
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Acknowledgements
This study was funded, designed and supervised by scientists at Bristol-Myers Squibb and AstraZeneca, the discoverers and developers of saxagliptin. David M. Kornhauser was an employee of Bristol-Myers Squibb until October 2006 and an employee of Icon Development Solutions until July 2007. Lorna Castaneda was an employee of Bristol-Myers Squibb until November 2009. Nimish N. Vachharajani is now an employee of Advinus Therapeutics (Bangalore, Karnataka, India). David W. Boulton, Li Li, Ernst U. Frevert, Angela Tang and Chirag G. Patel are current employees of Bristol-Myers Squibb and at the time that this work was conducted, all authors were employed by Bristol-Myers Squibb. The authors gratefully acknowledge the contributions of Thomas Marbury, MD (Orlando Clinical Research Center, Orlando, FL, USA); Ernesto Fuentes, MD (Elite Research Institute, Miami, FL, USA); and Sherwyn L. Schwartz, MD (Diabetes and Glandular Disease Research Associates, Inc., San Antonio, TX, USA) in the clinical conduct of the study, and the contribution of Daisy Whigan, MS (Bristol-Myers Squibb R&D, Princeton, NJ, USA) for her oversight of the bioanalytical work associated with this study. Technical and editorial assistance for this manuscript was provided by Gina Coviello, MS (Quintiles Medical Communications, Parsippany, NJ, USA).
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Boulton, D., Li, L., Frevert, E.U. et al. Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Saxagliptin. Clin Pharmacokinet 50, 253–265 (2011). https://doi.org/10.2165/11584350-000000000-00000
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DOI: https://doi.org/10.2165/11584350-000000000-00000