Monograph

A10BH05 - Linagliptin

Propably not porphyrinogenic

Rationale

Linagliptin is a substrate for CYP 3A4, and in vitro studies have shown that it is a weak competitive and mechanism-based inhibitor of CYP 3A4. The week inhibitory effect is not expected or found to have clinical relevance, and it is also regarded as insignificant in relevance of having any porphyrinogenic potential.

Chemical description

Linagliptin is a dipeptidyl peptidase-4 inhibitor.

Therapeutic characteristics

Linagliptin is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults. It is administered orally.

Metabolism and pharmacokinetics

Linagliptin is a substrate of CYP 3A4, but most of the drug is excreted unchanged. Linagliptin does not induce any CYP enzymes (Sheen 2010, SPC, Tornio 2012). In an in vitro study linagliptin was identified as a weak competitive and a moderate to poor mechanism-based inhibitor of CYP3A4. Linagliptin is not expected to cause clinically significant CYP related drug-drug interactions (Blech 2010, Golightly 2012), and is not listed as a perpetrator drug in interaction databases. Linagliptin had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate simvastatin (Graefe-Mody 2010). Concomitant administration of linagliptin and warfarin had no clinically relevant effect on the pharmacokinetics and pharmacodynamics of warfarin (Graefe-Mody 2011a). Coadministration of linagliptin and glyburide showed no clinically relevant inhibition CYP2C9 or CYP3A4 (Graefe-Mody 2011b).

References

#	Citation details	PMID
*	Scientific articles
1.	Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue).	19934256
2.	The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 2010 Apr; 38 (4): 667-78 Blech S, Ludwig-Schwellinger E, et al.
3.	Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Golightly LK, Drayna CC, et al. Clin Pharmacokinet. 2012 Aug 1;51(8):501-14.
4.	Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Int J Clin Pharmacol Ther. 2011a May;49(5):300-10. Graefe-Mody EU, Brand T, et al.
5.	Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin. Graefe-Mody U, Huettner S et al. Int J Clin Pharmacol Ther. 2010 Jun;48(6):367-74.	20497745
6.	Clinical pharmacokinetics and pharmacodynamics of linagliptin. Graefe-Mody U, Retlich S et al. Clin Pharmacokinet. 2012 Jul 1;51(7):411-27. Bestilt: PMI: 20497745
7.	Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin and a sulfonylurea, glyburide, in healthy subjects. Drug Metab Pharmacokinet. 2011b; 26(2):123-9. Graefe-Mody U, Rose P, et al.
8.	Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Scheen AJ. Diabetes Obes Metab. 2010 Aug; 12(8):648-58.	20590741
9.	Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications. Tornio A, Niemi M, et al. Trends Pharmacol Sci. 2012 Jun;33(6):312-22.	22475684
*	Drug interaction databases
10.	Lexi-Interact, via UpToDate.
11.	Micromedex® 2.0 (online). Drug Interactions). (14.12.2016).
12.	The Danish Health and Medicines Authority. The drug interaction database.
*	Summary of Product Characteristics
13.	The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Trajenta. (Last edition: October 2012).

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Netherlands

Linagliptine · Linagliptine Intas 5 mg filmomhulde tabletten · Linagliptine Viatris 5 mg, filmomhulde tabletten · Trajenta · Trajenta 5 mg filmomhulde tabletten

Belgium