Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Saxagliptin

• Published in: Clinical pharmacokinetics Vol. 50; no. 4; pp. 253 - 265
• Main Authors: Boulton, David, Li, Li, Frevert, Ernst U., Tang, Angela, Castaneda, Lorna, Vachharajani, Nimish N., Kornhauser, David M., Patel, Chirag G.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2011; Adis International; Wolters Kluwer Health, Inc; Springer Nature B.V
• Subjects: Adamantane - adverse effects; Adamantane - analogs & derivatives; Adamantane - analysis; Adamantane - blood; Adamantane - pharmacokinetics; Adamantane - urine; Adult; Aged; Biological and medical sciences; Complications and side effects; Diabetes Mellitus, Type 2 - drug therapy; Dialysis Solutions - chemistry; Dipeptides - adverse effects; Dipeptides - analysis; Dipeptides - blood; Dipeptides - pharmacokinetics; Dipeptides - urine; Dipeptidyl-Peptidase IV Inhibitors - adverse effects; Dipeptidyl-Peptidase IV Inhibitors - analysis; Dipeptidyl-Peptidase IV Inhibitors - pharmacokinetics; Dosage and administration; Female; Gastroenterology. Liver. Pancreas. Abdomen; General pharmacology; Half-Life; Hepatic Insufficiency - blood; Hepatic Insufficiency - metabolism; Hepatic Insufficiency - urine; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - analysis; Hypoglycemic Agents - pharmacokinetics; Internal Medicine; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - therapy; Liver diseases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Original Research Article; Other diseases. Semiology; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Physiological aspects; Renal Dialysis; Renal failure; Renal Insufficiency - blood; Renal Insufficiency - metabolism; Renal Insufficiency - urine; Saxagliptin; Severity of Illness Index; United States; Normal Renal Function; Severe Renal Impairment; Renal Impairment; Hepatic Impairment; Saxagliptin; Dipeptidyl-peptidase IV; Kidney disease; Human; Urinary system disease; Enzyme; Enzyme inhibitor; Hepatic disease; Peptidases; Hypoglycemic agent; Liver failure; Nephropathy; Gliptine derivatives; Renal failure; Hydrolases; Dipeptidyl-peptidase IV inhibitor; Digestive diseases; Pharmacokinetics
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.2165/11584350-000000000-00000

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 (CL CR ) 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 (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.