M Niemi1, J T Backman, M Neuvonen, P J Neuvonen. 1. Department of Clinical Pharmacology, Helsinki University Central Hospital, P.O. Box 340, 00029, HUS, Finland.
Abstract
AIMS/HYPOTHESIS: Our aim was to investigate possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide. METHODS: 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. RESULTS:Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5- to 15.0-fold; p<0.001) and prolonged its half-life (t(1/2)) from 1.3 to 3.7 h (p<0.001). Although itraconazole alone raised repaglinide AUC only 1.4-fold (1.1- to 1.9-fold; p<0.001), the gemfibrozil-itraconazole combination raised it 19.4-fold (12.9- to 24.7-fold) and prolonged the t(1/2) of repaglinide to 6.1 h (p<0.001). Plasma repaglinide concentration at 7 h was increased 28.6-fold by gemfibrozil and 70.4-fold by the gemfibrozil-itraconazole combination (p<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. CONCLUSION/ INTERPRETATION: 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.
RCT Entities:
AIMS/HYPOTHESIS: Our aim was to investigate possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide. METHODS: 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. RESULTS:Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5- to 15.0-fold; p<0.001) and prolonged its half-life (t(1/2)) from 1.3 to 3.7 h (p<0.001). Although itraconazole alone raised repaglinide AUC only 1.4-fold (1.1- to 1.9-fold; p<0.001), the gemfibrozil-itraconazole combination raised it 19.4-fold (12.9- to 24.7-fold) and prolonged the t(1/2) of repaglinide to 6.1 h (p<0.001). Plasma repaglinide concentration at 7 h was increased 28.6-fold by gemfibrozil and 70.4-fold by the gemfibrozil-itraconazole combination (p<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. CONCLUSION/ INTERPRETATION: 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.
Authors: Tanja Busk Bidstrup; Inga Bjørnsdottir; Ulla Grove Sidelmann; Mikael Søndergård Thomsen; Kristian Tage Hansen Journal: Br J Clin Pharmacol Date: 2003-09 Impact factor: 4.335
Authors: Joseph E Rower; Lane R Bushman; Kyle P Hammond; Rajendra S Kadam; Christina L Aquilante Journal: Biomed Chromatogr Date: 2010-12 Impact factor: 1.902
Authors: Mikko Niemi; Aleksi Tornio; Marja K Pasanen; Hanna Fredrikson; Pertti J Neuvonen; Janne T Backman Journal: Eur J Clin Pharmacol Date: 2006-04-27 Impact factor: 2.953