Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide

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Abstract
Our aim was to investigate possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide. In a randomised crossover study, 12 healthy volunteers received twice daily for 3 days either 600 mg gemfibrozil, 100 mg itraconazole (first dose 200 mg), both gemfibrozil and itraconazole, or placebo. On day 3 they ingested a 0.25 mg dose of repaglinide. Plasma drug and blood glucose concentrations were followed for 7 h and serum insulin and C-peptide concentrations for 3 h postdose. Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5- to 15.0-fold; p1/2) from 1.3 to 3.7 h (pp1/2 of repaglinide to 6.1 h (pp<0.001). Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide; i.e., repaglinide became a long-acting and stronger antidiabetic. Clinicians should be aware of this previously unrecognised and potentially hazardous interaction between gemfibrozil and repaglinide. Concomitant use of gemfibrozil and repaglinide is best avoided. If the combination is considered necessary, repaglinide dosage should be greatly reduced and blood glucose concentrations carefully monitored.