Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor

详细信息    查看全文

• 作者：David W. Boulton
• 刊名：Clinical Pharmacokinetics
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：56
• 期：1
• 页码：11-24
• 全文大小：
• 刊物主题：Pharmacotherapy; Pharmacology/Toxicology; Internal Medicine;
• 出版者：Springer International Publishing
• ISSN：1179-1926
• 卷排序：56

文摘

Saxagliptin is an orally active, highly potent, selective and competitive dipeptidyl peptidase (DPP)-4 inhibitor used in the treatment of type 2 diabetes mellitus at doses of 2.5 or 5 mg once daily. DPP-4 is responsible for degrading the intestinally derived hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 increases intact plasma GLP-1 and GIP concentrations, augmenting glucose-dependent insulin secretion. Both saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, demonstrate high degrees of selectivity for DPP-4 compared with other DPP enzymes. Saxagliptin is orally absorbed and can be administered with or without food. The half-life of plasma DPP-4 inhibition with saxagliptin 5 mg is ~27 h, which supports a once-daily dosing regimen. Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5 and is eliminated by a combination of renal and hepatic clearance. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with hepatic impairment. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with mild renal impairment, whereas dose reduction is recommended in patients with moderate or severe renal impairment because of greater systemic exposure [the area under the plasma concentration–time curve (AUC)] to saxagliptin total active moieties. Clinically relevant drug–drug interactions have not been detected; however, limiting the dose to 2.5 mg once daily is recommended in the USA when saxagliptin is coadministered with strong CYP inhibitors, because of increased saxagliptin exposure. In summary, saxagliptin has a predictable pharmacokinetic and pharmacodynamic profile.