Bioequivalence of Linagliptin 5 mg Once Daily and 2.5 mg Twice Daily: Pharmacokinetics and Pharmacodynamics in an Open-label Crossover Trial

Abstract

Purpose:

Linagliptin is an oral antihyperglycemic drug that acts by inhibiting the dipeptidyl peptidase-4 enzyme. A 5-mg once-daily regimen is available, but an alternative regimen was needed for twice-daily fixed-dose combinations. Although linagliptin has non-linear pharmacokinetics, simulation suggested 2.5 mg twice-daily would provide bioequivalent exposure and comparable plasma dipeptidyl peptidase-4 inhibition to 5 mg once-daily.

Methods:

This crossover study compared steady-state pharmacokinetics and pharmacodynamics of linagliptin 5 mg once-daily and 2.5 mg twice-daily, both administered for 7 days.

Results:

In total, 16 healthy volunteers entered the study, and 15 completed both treatment periods. Exposure over 24-h at steady state (AUC_0–24,ss) was similar for linagliptin 5 mg once-daily and 2.5 mg twice-daily (132 vs. 124 nmol · h/L), and the 90% confidence interval of the adjusted geometric mean ratio of AUC_0–24,ss was well within the acceptance range for bioequivalence (ratio 93.9%; 90% confidence interval 89.5, 98.5). Median dipeptidyl peptidase-4 inhibition over a 24-h interval at steady state was 85.9% with linagliptin 5 mg once-daily and 86.5% with 2.5 mg twice-daily, and median dipeptidyl peptidase-4 inhibition values were approximately 80.0% at trough. Most subjects had no adverse events and there were no serious adverse events.

Conclusions:

Linagliptin 5 mg once-daily and 2.5 mg twice-daily provided bioequivalent exposure and similar inhibition of dipeptidyl peptidase-4 over the whole dosing interval.

Key words

linagliptin - metformin - diabetes - fixed-dose combination - pharmacokinetics - pharmacodynamics

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