Effect of a High‐Fat Meal on the Pharmacokinetics of Saxagliptin in Healthy Subjects

Abstract

1211S axagliptin is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme. DPP-4 is an enzyme that selectively cleaves dipeptides such as the key insulinotropic hormone glucagonlike peptide-1 (GLP-1), converting it from the intact and active form to the inactive form, and is responsible for the short half-life of intact GLP-1 in vivo. 1 Inhibitors of DPP-4 increase levels of endogenous intact GLP-1 and prolong its physiological actions, augmenting postprandial insulin secretion and improving the glycemic profile in patients with type 2 diabetes. 2 Because GLP-1 stimulates insulin secretion in a glucose-dependent manner, DPP-4 inhibitors are expected to present lower risks of hypoglycemia and may not lead to weight gain.Saxagliptin is a Biopharmaceutics Classification System (BCS) class III compound (high solubility/low permeability) but exhibits class-I−like characteristics. Clinical studies have shown that saxagliptin is rapidly and almost completely absorbed following oral administration. 3 Saxagliptin is metabolized by cytochrome P450 enzymes 3A4 and 3A5 (CYP3A4 and CYP3A5) to the pharmacologically active major metabolite BMS-510849. 4 In vitro experiments indicate that saxagliptin is a weak substrate for the efflux transporter P-glycoprotein (P-gp). 5 The terminal half-life of saxagliptin in humans is approximately 2.5 hours. 3 Food-drug interactions can result in 2 predominant clinical effects. The first is decreased bioavailability, resulting in the increased possibility of treatment failure; conversely, there is the possibility of increased bioavailability, with increased risk of adverse events and toxicities. 6 A classic example of a food-drug interaction resulting in decreased bioavailability with eventual treatment failure is that of tetracycline administration with milk. The calcium ions present in milk sequester the tetracycline, thereby decreasing its absorption from the gastrointestinal (GI) tract and leading to subtherapeutic systemic exposures, predisposing patients to treatment failure. 7 Another important food-drug interaction involves the effects of food or its constituents on metabolic enzyme activity. Most commonly observed with foods such as grapefruit juice, red wine, and tea are metabolic CYP3A4-based food-drug interactions. These foods contain furanocoumarins and flavonoids, which have been shown to inhibit the CYP3A4 enzyme system, 8 consequently slowing drug metabolism and increasing systemic drug exposure.In a preliminary study with a capsule formulation of saxagliptin, administration of single oral doses of 5 to 20 mg of saxagliptin following a highfat meal resulted in modest effects, including a maximum decrease of 28% in the maximum (peak) plasma drug concentration (C max ) of saxagliptin and a 32% increase in the area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) of saxagliptin compared with the fasted state. The time to reach C max (T max ) was increased by approximately 1.25...

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

“…In comparison with the fasted state, administration of saxagliptin with a high-fat meal did not affect the C max of saxagliptin, but the median time to reach the C max (t max ) of saxagliptin was prolonged by approximately 0.5 h [31]. After a high-fat meal, the AUC from time zero extrapolated to infinity (AUC ? )…”

“…The somewhat higher AUC value for saxagliptin observed when saxagliptin is taken after a high-fat meal compared with the fasted state is unlikely to result in clinically meaningful alterations in the safety and tolerability profile or the efficacy profile of saxagliptin. Therefore, saxagliptin can be taken without regard to food intake [31].…”

Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus

“…62 Ketoconazole is a broad-spectrum antif ungal agent and a potent inhibitor of CYP3A4/5, which might be expected to alter the pharmacokinetics of saxagliptin. 65 Boulton et al 64 concluded that no dosage adjustment would be required when these two drugs are coadministered.…”

Saxagliptin for type 2 diabetes

“…Exposure to 5-hydroxy saxagliptin, however, was reduced by 88%. 26 Based on these findings, reducing the dose of saxagliptin to 2.5 mg once daily for patients who are concomitantly taking ketoconazole or another strong CYP 3A4/5 inhibitor is recommended. 1 Concomitant administration of long-acting diltiazem (360 mg once daily for nine days), a moderate CYP 3A4/5 inhibitor, with a single 10 mg dose of saxagliptin significantly increased the C max and AUC ∞ of saxagliptin by 63% and 109%, respectively, compared with the administration of saxagliptin alone.…”