Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor.
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.
Quantitative Clinical Pharmacology, Early Clinical Development, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA. david.boulton2@astrazeneca.com.
David W
DW
Boulton
D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate
D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D052216:Glucagon-Like Peptide 1; C502994:saxagliptin; D051544:Cytochrome P-450 CYP3A; D000218:Adamantane