Influence of Drugs Interacting with CYP3A4 on the Pharmacokinetics, Pharmacodynamics, and Safety of the Prandial Glucose Regulator Repaglinide

Abstract

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.

Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects

“…Similar to isavuconazole, posaconazole does not inhibit CYP1A2, CYP2C8, or CYP2D6 activity 38. In addition, coadministration with ketoconazole causes only minor increases (∼15%) in repaglinide exposure 39. No studies have evaluated interactions between bupropion and the triazole antifungal agents.…”

Prevalence of Metabolic Syndrome in Organ Transplantation: A Review of the Literature

“…More recently, during the A Diabetic Outcome Progression Trial (ADOPT) conducted to compare glycemic control in patients on rosiglitazone, metformin, or glyburide, a higher incidence of fractures in the upper arm, hand, and foot was noted among female patients treated with rosiglitazone [146,147]. Subsequently, pioglitazone was also recognized to be associated with a similar increased risk of fracture in women but not in men, although further studies are needed [147].…”

‘The tubercular diabetic’

“…We would encourage Quantrill and Webbe to publish their findings in more detail so that others can build on them further. 5 but like isoniazid, it may increase insulin requirements. 6 Liver and nerve toxicity from anti-TB drugs may be difficult to distinguish from diabetes-associated non-alcoholic fatty liver disease and peripheral neuropathy respectively and for those with co-morbid HIV infection with access to treatment, there is the added complication of antiretroviral-associated insulin resistance.…”