Linaglyptin (Linagliptinum)

Metformin. The combined use of metformin (repeated daily dose intake of 850 mg 3 times a day) and linagliptin 10 mg once daily (above the therapeutic dose) in healthy volunteers did not lead to clinically significant changes in the pharmacokinetics of linagliptin or metformin. In this way, linaglyptin It is not an inhibitor of the transport of organic cations.

Derivatives of sulfonylureas. The pharmacokinetics of linagliptin (5 mg) did not change when combined with glibenclamide (a single dose of 1.75 mg) and multiple intake of linagliptin by mouth (5 mg each). However, there was a clinically insignificant decrease in AUC and C_max glibenclamide by 14%. Because the glibenclamide is metabolized mainly by CYP2C9, these data also support the conclusion that linaglyptin is not an inhibitor of CYP2C9. Clinically significant interactions with other sulfonylurea derivatives (for example,glipizide and glimepiride), which, like glibenclamide, are mainly metabolized with the participation of CYP2C9.

Thiazolidinediones. The combined use of several doses of linagliptin 10 mg per day (above the therapeutic dose) and pioglitazone at 45 mg per day (multiple administration), which is a substrate for CYP2C8 and CYP3A4, did not have a clinically significant effect on the pharmacokinetics of linagliptin or pioglitazone or active metabolites of pioglitazone . This indicates that linagliptin in vivo is not an inhibitor of the metabolism mediated by CYP2C8 and confirms the conclusion that there is no significant inhibitory effect of linagliptin in vivo on CYP3A4.

Ritonavir. The combined use of linagliptin (a single dose of 5 mg orally) and ritonavir (repeated intake of 200 mg orally), an active P-glycoprotein inhibitor and CYP3A4 isoenzyme, increased the AUC and C_max linagliptin approximately in 2 times and in 3 times accordingly. However, these changes in the pharmacokinetics of linagliptin were not considered significant. Therefore, clinically significant interaction with other inhibitors of P-glycoprotein and CYP3A4 is not expected, and dose changes are not required.

Rifampicin.Multiple combined use of linagliptin and rifampicin, the active inducer of the P-glycoprotein and the isoenzyme CYP3A4, led to a decrease in AUC and C_max linagliptin by 39.6% and 43.8%, respectively, and to a decrease in inhibition of the basal activity of dipeptidyl peptidase-4 by approximately 30%. Thus, it is expected that the clinical efficacy of linagliptin, used in combination with active inducers of the P-glycoprotein, will persist, although it may not manifest itself fully.

Digoxin. Joint repeated use in healthy volunteers of linagliptin (5 mg per day) and digoxin (0.25 mg per day) had no effect on the pharmacokinetics of digoxin. In this way, linaglyptin in vivo is not an inhibitor of transport mediated by P-glycoprotein.

Warfarin. Linaglyptin, applied multiple times at a dose of 5 mg per day, did not alter the pharmacokinetics of warfarin, a substrate for CYP2C9, indicating that linagliptin lacks the ability to inhibit CYP2C9.

Simvastatin. Linaglyptin, used in healthy volunteers many times at a dose of 10 mg per day (above the therapeutic dose), had a minimal effect on the pharmacokinetic parameters of simvastatin, which is a sensitive substrate for CYP3A4.After receiving 10 mg of linagliptin together with simvastatin, used in a daily dose of 40 mg for 6 days, the value of AUC of simvastatin increased by 34%, and the magnitude C_max - on 10 %. In this way, linaglyptin is a weak inhibitor of the metabolism mediated by CYP3A4. A dose change when taken concomitantly with drugs that are metabolized with CYP3A4 is considered impractical.

Oral contraceptive preparations. The combined use of lignagliptin at a dose of 5 mg with levonorgestrel or ethinyl estradiol did not alter the pharmacokinetics of these drugs.