Journal Article

Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Saxagliptin

Frevert, Ernst U., Kornhauser, David M., Li, Li, Castaneda, Lorna, Boulton, David, Tang, Angela, Vachharajani, Nimish N., Patel, Chirag G.

2011

Overview

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.

• Publisher: Springer International Publishing,Adis International,Wolters Kluwer Health, Inc,Springer Nature B.V
• Subject: 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