Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide.
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.
Hatorp
Vibeke
V
Clinical Development and Drug Metabolism Departments, Novo Nordisk A/S, Bagsvaerd, Denmark.
Hansen
Kristian T
KT
Thomsen
Mikael S
MS
D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology
D001786:Blood Glucose; D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; C072379:repaglinide; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D012293:Rifampin