Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide

J Clin Pharmacol. 2003 Jun;43(6):649-60.


The object of this study was to analyze drug interactions between repaglinide, a short-acting insulin secretagogue, and five other drugs interacting with CYP3A4: ketoconazole, rifampicin, ethinyloestradiol/levonorgestrel (in an oral contraceptive), simvastatin, and nifedipine. In two open-label, two-period, randomized crossover studies, healthy subjects received repaglinide alone, repaglinide on day 5 of ketoconazole treatment, or repaglinide on day 7 of rifampicin treatment. In three open-label, three-period, randomized crossover studies, healthy subjects received 5 days of repaglinide alone; 5 days of ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine alone; or 5 days of repaglinide concomitant with ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. Compared to administration of repaglinide alone, concomitant ketoconazole increased mean AUC0-infinity for repaglinide by 15% and mean Cmax by 7%. Concomitant rifampicin decreased mean AUC0-infinity for repaglinide by 31% and mean Cmax by 26%. Concomitant treatment with CYP3A4 substrates altered mean AUC0-5 h and mean Cmax for repaglinide by 1% and 17% (ethinyloestradiol/levonorgestrel), 2% and 27% (simvastatin), or 11% and 3% (nifedipine). Profiles of blood glucose concentration following repaglinide dosing were altered by less than 8% by both ketoconazole and rifampicin. In all five studies, most adverse events were related to hypoglycemia, as expected in a normal population given a blood glucose regulator. The safety profile of repaglinide was not altered by pretreatment with ketoconazole or rifampicin or by coadministration with ethinyloestradiol/levonorgestrel. The incidence of adverse events increased with coadministration of simvastatin or nifedipine compared to either repaglinide or simvastatin/nifedipine treatment alone. No clinically relevant pharmacokinetic interactions occurred between repaglinide and the CYP3A4 substrates ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. The pharmacokinetic profile of repaglinide was altered by administration of potent inhibitors or inducers, such as ketoconazole or rifampicin, but to a lesser degree than expected. These results are probably explained by the metabolic pathway of repaglinide that involves other enzymes than CYP3A4, reflected to some extent by a small change in repaglinide pharmacodynamics. Thus, careful monitoring of blood glucose in repaglinide-treated patients receiving strong inhibitors or inducers of CYP3A4 is recommended, and an increase in repaglinide dose may be necessary. No safety concerns were observed, except a higher incidence in adverse events in patients receiving repaglinide and simvastatin or nifedipine.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • Blood Glucose / drug effects
  • Carbamates* / blood
  • Carbamates* / pharmacokinetics
  • Carbamates* / pharmacology
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / drug effects*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions*
  • Female
  • Half-Life
  • Humans
  • Hypoglycemic Agents* / blood
  • Hypoglycemic Agents* / pharmacokinetics
  • Hypoglycemic Agents* / pharmacology
  • Ketoconazole / pharmacology
  • Male
  • Piperidines* / blood
  • Piperidines* / pharmacokinetics
  • Piperidines* / pharmacology
  • Rifampin / pharmacology
  • Simvastatin / pharmacology


  • Blood Glucose
  • Carbamates
  • Hypoglycemic Agents
  • Piperidines
  • repaglinide
  • Cytochrome P-450 Enzyme System
  • Simvastatin
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ketoconazole
  • Rifampin