OBJECT DRUGS

Antidiabetic Agents (CYP2C8 Substrates):

• Pioglitazone (Actos)
• Repaglinide (Prandin)
• Rosiglitazone (Avandia)

PRECIPITANT DRUGS

• Clopidogrel (Plavix)
• Deferasirox (Exjade)
• Gemfibrozil (Lopid)
• Lapatinib (Tykerb)

Comment:

Gemfibrozil markedly increases plasma concentrations of repaglinide, probably through gemfibrozil-induced inhibition of CYP2C8 and probably UGT (the role of OATP1B1 is under investigation). Clopidogrel and deferasirox inhibit CYP2C8 and have also been shown to increase plasma concentrations of repaglinide about 5-fold and 2-fold respectively. Lapatinib is also a CYP2C8 inhibitor, and is likely to interact with these antidiabetic agents. These combinations would be expected to increase the risk of hypoglycemia. The inhibitory effect of gemfibrozil on repaglinide metabolism appears to last at least 12 hours, well after the gemfibrozil is largely eliminated. When a potent CYP3A4 inhibitor (itraconazole) was given in addition to gemfibrozil, plasma concentrations of repaglinide were increased almost 20-fold.

Class 2: Use only if benefit felt to outweigh risk

• Use Alternative:It would be prudent to use an alternative to one of the drugs.
• Gemfibrozil: Little is known about the effect of fibrates other than gemfibrozil on repaglinide pharmacokinetics. In vitro studies suggest that fenofibrate (Tricor) may also inhibit the CYP2C8 metabolism of repaglinide, but perhaps to a lesser degree.
• Repaglinide: Study in healthy subjects suggests that gemfibrozil has little effect on nateglinide (Starlix) metabolism. Gemfibrozil would be expected to have little or no effect on many other antidiabetics given that most of them are metabolized primarily by enzymes other than CYP2C8.
• Circumvent/Minimize: Consider using conservative doses of repaglinide if it is used concurrently with gemfibrozil.
• Monitor: In patients receiving repaglinide, monitor blood glucose carefully if gemfibrozil is started, stopped, or changed in dosage.