A Randomized, Open-Label, Crossover Study Evaluating the Effect of Food on the Relative Bioavailability of Linagliptin in Healthy Subjects

Abstract

Objective The objective of this study was to determine the relative bioavailability of the dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin when administered with and without food, in accordance with regulatory requirements to support dosing recommendations for patients. Methods This was a randomized, open-label, crossover study involving 32 healthy white male and female subjects. All subjects received a single dose of 5 mg linagliptin after an overnight fast of at least 10 hours, or immediately after ingestion of a high-fat, high-calorie breakfast. These treatments were separated by a period of 5 weeks. Plasma samples for pharmacokinetic analysis were collected before dosing and at prespecified time points after dosing. The concentration of linagliptin in these samples was analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry. Relative bioavailability was assessed by the total area under the curve between 0 and 72 hours (AUC 0–72) and maximum measured plasma concentration (C max) of linagliptin. Tolerability was also assessed. Results In 32 subjects (mean age, 34.8 years; weight, 74.3 kg; male, 53%; white race, 100%), intake of a high-fat meal resulted in comparable bioavailability with regard to AUC 0–72 (geometric mean ratio [GMR] between the fed and fasted group means was 103.5%; 90% CI, 98.1%–109.2%). Individuals' responses to food ranged from a maximum increase in exposure of 38% to a decrease of 32% relative to the fasted state. The concurrent intake of food increased the time to reach maximum plasma concentration (T max) by approximately 2 hours and reduced C max by about 15% (GMR 84.7%; 90% CI, 75.9%–94.6%). Since adequate drug exposure for inhibition of DPP-4 was still given for the entire 24-hour dosing interval, this result was considered to be of no clinical relevance. Linagliptin was well tolerated during the study. Conclusions Intake of a high-fat meal reduced the rate of linagliptin absorption but had no influence on the extent of absorption; this finding suggests that food has no relevant influence on the efficacy of linagliptin.