title: Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin.
abstract: 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 antihyperglycaemic 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 5 mg (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.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA. david.boulton@bms.com
authors.forename: David W
authors.initials: DW
authors.lastname: Boulton
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Ernst U
authors.initials: EU
authors.lastname: Frevert
authors.forename: Angela
authors.initials: A
authors.lastname: Tang
authors.forename: Lorna
authors.initials: L
authors.lastname: Castaneda
authors.forename: Nimish N
authors.initials: NN
authors.lastname: Vachharajani
authors.forename: David M
authors.initials: DM
authors.lastname: Kornhauser
authors.forename: Chirag G
authors.initials: CG
authors.lastname: Patel
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015314:Dialysis Solutions / Q000737:chemistry; D004151:Dipeptides / Q000009:adverse effects / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D048550:Hepatic Insufficiency / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000378:metabolism / Q000628:therapy; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism* / Q000652:urine; D012720:Severity of Illness Index
chemical_list: C558749:5-hydroxysaxagliptin; D015314:Dialysis Solutions; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; C502994:saxagliptin; D000218:Adamantane