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

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.

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

“…not metabolized). For instance, if a drug has high renal clearance as a percentage of total body clearance in an unchanged form, then mild or moderate renal impairment could alter AUC by twofold or more [5,6]. Conversely, where the percent unchanged drug (or active metabolite) excreted in urine is low, then severe renal impairment may have no effect [7].…”

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“…Saxagliptin is used adjunctively with diet and exercise in patients with T2DM as monotherapy; as add‐on combination therapy with metformin, sulfonylureas, thiazolidinediones, and sodium‐glucose cotransporter‐2 inhibitors; and, in some countries, as initial combination therapy with metformin . In most countries, the usual clinical dose in adults with normal renal function or mild renal impairment is 5 mg administered orally once daily …”

“…It is eliminated by a combination of metabolism (∼77% of dose, mainly via CYP3A4/5), and renal excretion (∼23% of dose excreted in urine as parent saxagliptin, including an active renal secretion component) with terminal half‐life of about 7 hours . Saxagliptin has a major active metabolite, 5‐hydroxy saxagliptin, which has plasma systemic exposure ∼3‐fold greater (range, 1.7‐ to 6.9‐fold) than that of the parent drug . In vitro enzyme kinetic binding studies indicate that 5‐hydroxy saxagliptin is approximately 2‐fold less potent than parent saxagliptin with respect to DPP‐4 inhibition .…”

“…In vitro enzyme kinetic binding studies indicate that 5‐hydroxy saxagliptin is approximately 2‐fold less potent than parent saxagliptin with respect to DPP‐4 inhibition . Thus, when the clinical pharmacology profile of saxagliptin is considered, particularly in situations in which the metabolite‐to‐parent ratio is altered relative to a reference state or population (eg, drug‐drug interactions as a result of altered cytochrome P450 [CYP] 3A4/5 activity and specific populations), it is important to consider the pharmacokinetics of 5‐hydroxy saxagliptin, as well as those of the parent drug . In situations in which CYP3A4/5 is induced, such as with rifampin (rifampicin), the saxagliptin:5‐hydroxy saxagliptin ratio is decreased, but the overall plasma DDP‐4 inhibition activity is not markedly affected because of the presence of greater systemic exposures of the active metabolite and no dose adjustment for saxagliptin is recommended .…”

“…5 Saxagliptin has a major active metabolite, 5-hydroxy saxagliptin, which has plasma systemic exposure ß3-fold greater (range, 1.7-to 6.9-fold) than that of the parent drug. 4 In vitro enzyme kinetic binding studies indicate that 5-hydroxy saxagliptin is approximately 2-fold less potent than parent saxagliptin with respect to DPP-4 inhibition. 9 Thus, when the clinical pharmacology profile of saxagliptin is considered, particularly in situations in which the metabolite-to-parent ratio is altered relative to a reference state or population (eg, drug-drug interactions as a result of altered cytochrome P450 [CYP] 3A4/5 activity and specific populations), it is important to consider the pharmacokinetics of 5-hydroxy saxagliptin, as well as those of the parent drug.…”