Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers

Abstract

The aim of this study was to investigate whether multiple doses of the oral and highly selective dipeptidyl peptidase-4 inhibitor linagliptin affect the steady-state pharmacokinetics of the P-glycoprotein substrate digoxin. This single-center, open-label, two-period cross-over study involved healthy subjects (n = 20), randomized to treatment sequence AB or BA, where A comprised 0.25 mg digoxin qd for 5 days, then 0.25 mg digoxin qd plus 5 mg linagliptin qd for 6 days, and B comprised 0.25 mg digoxin qd for 11 days. A treatment-free period (≥35 days for AB and 14 days for BA) separated each treatment in both sequences. There were no clinically significant changes in steady-state pharmacokinetic parameters of digoxin when it was co-administered with linagliptin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUC(τ,ss), C (max,ss) and renal clearance (CL( R,0-24,ss)) of digoxin were all within the bioequivalence range 80-125%, which is important as digoxin has a narrow therapeutic range. There was a low incidence of adverse events, which were randomly distributed between treatment groups. In conclusion, linagliptin did not alter the pharmacokinetics of digoxin in this study, indicating that linagliptin does not inhibit P-glycoprotein or other transporters relevant for digoxin pharmacokinetics. These results suggest that linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated.

In Vitro Predictability of Drug-Drug Interaction Likelihood of P-Glycoprotein-Mediated Efflux of Dabigatran Etexilate Based on [I]2/IC50 Threshold

“…These assessments using in-house in vitro IC 50 data were consistent with findings of clinical interaction studies using digoxin as a P-gp probe drug in a way that AUC i /AUC for these six drugs was .1.25. On the other hand, the [I] 2 /IC 50 ratio of linagliptin was less than 10 and this assessment was in agreement with the absence of P-gp-mediated clinical DDI between digoxin and linagliptin (Friedrich et al, 2011).…”

Application of permeability-limited physiologically-based pharmacokinetic models: Part I–digoxin pharmacokinetics incorporating P-glycoprotein-mediated efflux

“…The thin lines represent individual trials ( n = 20) and the solid black line is the mean of the simulated population ( n = 220). The open circles are mean observed values 64,65…”

“…; bis in die or “twice a day”) or 0.5 mg (b.i.d.) were generated and the simulated profiles for digoxin were compared with those observed in six independent PK studies matching the dose regime simulated44,63–67,70 (Table 2). Inter‐individual concentration–time profiles: Twenty virtual trials of 10 male subjects aged 23–30 years receiving a single oral dose of 0.5 mg digoxin were generated.…”

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

“…Linagliptin did not change the pharmacokinetic steady state of ethinyl estradiol and levonorgestrel, 147 digoxin, 148 warfarin, 149 glyburide, 150 pioglitazone, 151 simvastatin, 152 and metformin. 117 Rifampicin, in turn, can reduce the exposure to linagliptin, suggesting that linagliptin efficacy may be reduced by concomitant use with rifampicin.…”