A10BD19 - Linagliptin and Empagliflozin

Propably not porphyrinogenic

Side effects

Empagliflozin: Genital and urinary tract infections are common side effects of empagliflozin that might potentially be porphyrinogenic.

Rationale

Linagliptin: 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. Empagliflozin: Empagliflozin is not an inducer or an inhibitor of CYP enzymes and is therefore probably not porphyrinogenic.

Chemical description

Linagliptin: Linagliptin is a dipeptidyl peptidase-4 inhibitor. Empagliflozin: Empagliflozin is a selective and reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2).

Therapeutic characteristics

Linagliptin: Linagliptin is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults. It is administered orally. Empagliflozin: Empagliflozin is an anti-diabetic indicated in adults with type 2 diabetes mellitus to improve glycaemic control. It is administered orally.

Metabolism and pharmacokinetics

Linagliptin: 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). Empagliflozin: In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Empagliflozin does not inhibit, inactivate, or induce CYP450 (FDA drug label). Interaction studies has not shown any potential for empagliflozin to affect the CYP metabolism of other drugs (Macha 2013a,b)

Similar drugs

Explore alternative drugs in similar therapeutic classes A10B / A10BD or go back.

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.	Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers. Diabetes Obes Metab. 2013a Apr;15(4):316-23. Macha S, Rose P, et al.
9.	Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clin Ther. 2013b Mar;35(3):226-35. Macha S, Sennewald R, et al.	23497760
10.	Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Scheen AJ. Diabetes Obes Metab. 2010 Aug; 12(8):648-58.	20590741
11.	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
*	Government bodies
12.	U.S. Food and Drug Administration (FDA). Label information. Jardiance. (Revised: December. 2015).
*	Drug interaction databases
13.	Lexi-Interact, via UpToDate.
14.	Micromedex® 2.0 (online). Drug Interactions). (14.12.2016).
15.	The Danish Health and Medicines Authority. The drug interaction database.
*	Summary of Product Characteristics
16.	The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Jardiance.
17.	The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Trajenta. (Last edition: October 2012).