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

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Abstract

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.

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Acknowledgments

Medical writing assistance was provided by Lauren D’Angelo, PhD, and Richard Edwards, PhD, from Complete Healthcare Communications, LLC (Chadds Ford, PA, USA), with funding from AstraZeneca.

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  1. Quantitative Clinical Pharmacology, Early Clinical Development, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA

    David W. Boulton

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Correspondence to David W. Boulton.

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Ethical standards

All studies were approved by an institutional review board before study initiation and were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. Before the beginning of each study, all subjects provided written informed consent.

Disclosures

Data from several studies, published and unpublished, are presented herein, and the author, David W. Boulton, had full control and access to all of the primary data. All data are available upon request. David W. Boulton is a stock holder and employee of AstraZeneca.

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Boulton, D.W. Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor. Clin Pharmacokinet 56, 11–24 (2017). https://doi.org/10.1007/s40262-016-0421-4

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