Trajenta Drug Interactions

In vitro assessment of drug interactions: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates.
In vivo assessment of drug interactions: Clinical data described as follows suggest that the risk for clinically meaningful interactions by coadministered medicinal products is low. No clinically significant interactions requiring dose adjustment were observed. Linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin or oral contraceptives providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter (OCT).
Metformin: Co-administration of multiple three-times-daily doses of 850 mg metformin with a supratherapeutic dose of 10 mg linagliptin once daily did not clinical meaningfully alter the pharmacokinetics of linagliptin or metformin in healthy volunteers. Therefore, linagliptin is not an inhibitor of OCT-mediated transport.
Sulphonylureas: The steady-state pharmacokinetics of 5 mg linagliptin were not changed by co-administration of a single 1.75 mg dose glibenclamide (glyburide) and multiple oral doses of 5 mg linagliptin. However there was a clinically not relevant reduction of 14% of both AUC and C_max of glibenclamide. Because glibenclamide is primarily metabolized by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically meaningful interactions would not be expected with other sulphonylureas (e.g. glipizide, tolbutamide and glimepiride) which, like glibenclamide, are primarily eliminated by CYP2C9.
Thiazolidinediones: Co-administration of multiple daily doses of 10 mg linagliptin (supratherapeutic) with multiple daily doses of 45 mg pioglitazone, a CYP2C8 and CYP3A4 substrate, had no clinically relevant effect on the pharmacokinetics of either linagliptin or pioglitazone or the active metabolites of pioglitazone, indicating that linagliptin is not an inhibitor of CYP2C8-mediated metabolism in vivo and supporting the conclusion that the in vivo inhibition of CYP3A4 by linagliptin is negligible.
Ritonavir: A study was conducted to assess the effect of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, on the pharmacokinetics of linagliptin. Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir increased the AUC and C_max of linagliptin approximately twofold and threefold, respectively. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir indicated that the increase in exposure will be not associated with an increased accumulation. These changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-glycoprotein/CYP3A4 inhibitors and dose adjustment is not required.
Rifampicin: A study was conducted to assess the effect of rifampicin, a potent inductor of P-glycoprotein and CYP3A4, on the pharmacokinetics of 5 mg linagliptin. Multiple co-administration of linagliptin with rifampicin, resulted in a 39.6% and 43.8% decreased linagliptin steady-state AUC and C_max and about 30% decreased DPP-4 inhibition at trough. Thus linagliptin in combination with strong P-gp inducers is expected to be clinically efficacious, although full efficacy might not be achieved.
Digoxin: Co-administration of multiple daily doses of 5 mg linagliptin with multiple doses of 0.25 mg digoxin had no effect on the pharmacokinetics of digoxin in healthy volunteers. Therefore, linagliptin is not an inhibitor of P-glycoprotein-mediated transport in vivo.
Warfarin: Multiple daily doses of 5 mg linagliptin did not alter the pharmacokinetics of S(-) or R(+) warfarin, a CYP2C9 substrate, showing that linagliptin is not an inhibitor of CYP2C9.
Simvastatin: Multiple daily doses of 10 mg linagliptin (supratherapeutic) had a minimal effect on the steady state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy volunteers.
Following administration of 10 mg linagliptin concomitantly with 40 mg of simvastatin daily for 6 days, the plasma AUC of simvastatin was increased by 34%, and the plasma C_max by 10%.
Therefore, linagliptin is considered to be a weak inhibitor of CYP3A4-mediated metabolism, and dosage adjustment of concomitantly administered substances metabolised by CYP3A4 is considered unnecessary.
Oral Contraceptives: Co-administration with 5 mg linagliptin did not alter the steady-state pharmacokinetics of levonorgestrel or ethinylestradiol.
The absolute bioavailability of linagliptin is approximately 30%. Because co-administration of a high-fat meal with linagliptin had no clinically relevant effect on the pharmacokinetics, linagliptin may be administered with or without food.