Vibeke Hatorp

Pharmacokinetics of repaglinide in subjects with renal impairment.

To evaluate the effect of renal impairment and renal failure on the pharmacokinetics and safety of repaglinide.

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‐∞ for repaglinide by 15% and mean Cmax by 7%. Concomitant rifampicin decreased mean AUC0‐∞ for repaglinide by 31% and mean Cmax by 26%. Concomitant treatment with CYP3A4 substrates altered mean AUC0–5h 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.

Absorption, metabolism and excretion of a single oral dose of (14)C-repaglinide during repaglinide multiple dosing

AbstractObjective: The present study was designed to assess the disposition of 14C-repaglinide in whole blood, plasma, urine and faeces, and to measure the total recovery of drug-related material in urine and faeces after a single 2-mg oral dose of 14C-repaglinide during multiple dosing. Methods: In this single-centre, open-label, phase-I trial, six healthy male volunteers received 2 mg of the prandial glucose regulator, repaglinide, four times daily for 13 days, 15 min before meals. On the morning of day 7, breakfast was omitted and the dose was given as an oral solution containing 2 mg of 14C-repaglinide. Results: After oral dosing, a mean peak plasma concentration of repaglinide of 27.74 ng · ml−1 (range: 16.84–36.65 ng · ml−1) was observed with a time to peak concentration of 0.5 h. Approximately 20% of repaglinide and its associated metabolites were distributed into red blood cells. No measurable 14C-radioactivity was present in whole blood samples 6 h after dosing. Within 96 h of dosing with 14C-repaglinide, 90% of the administered dose appeared in the faeces and 8% was excreted in urine. In the plasma, the major compound was repaglinide (61%). In the urine, the major metabolites were unidentified polar compounds, the aromatic amine (M1) (24%), and the dicarboxylic acid (M2) (22%). In the faeces, the major metabolite was M2 (66% of administered dose). Therefore, repaglinide was excreted predominantly as metabolites and the major in vivo metabolite of repaglinide in humans was M2. During regular dosing for 6 days, the morning plasma trough levels of repaglinide were, with very few exceptions, almost always too low to measure, indicating the absence of accumulation at this dose of 2 mg four times daily. Repaglinide was well tolerated, and there were no episodes of hypoglycaemia. Conclusion: After oral dosing with repaglinide, the mean peak plasma concentration was rapidly attained and, thereafter, plasma concentrations decreased promptly. The major route of excretion was via the faeces. These properties make repaglinide a suitable insulin secretagogue for all patients with type-2 diabetes who retain sufficient β-cell function.

Repaglinide pharmacokinetics in healthy young adult and elderly subjects

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.

Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease.

Repaglinide is a novel insulin secretagogue developed in response to the need for a fast‐acting, oral prandial glucose regulator for the treatment of type 2 (non‐insulin‐dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This open, parallel‐group study compared the pharmacokinetics and tolerability of a single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with chronic liver disease (CLD) (n = 12). Values for AUC and Cmax were significantly higher in CLD patients compared with healthy subjects, and the MRT was prolonged in CLD patients. Values for tmax did not differ between the groups, but t1/2 was significantly prolonged in CLD patients compared with previously determined values in healthy subjects. AUC was inversely correlated with caffeine clearance in CLD patients but not in healthy subjects. Blood glucose profiles were similar in both groups. Adverse events (principally hypoglycemia) were similar in the two groups; none was serious. Repaglinide clearance is significantly reduced in patients with hepatic impairment; the agent should be used with caution in this group.

Drug Interaction Studies with Repaglinide: Repaglinide on Digoxin or Theophylline Pharmacokinetics and Cimetidine on Repaglinide Pharmacokinetics

Drug interaction studies were carried out to ensure that hypoglycemia due to inhibition of repaglinide elimination or chronic hyperglycemia due to inhibition of repaglinide absorption was avoided. Conversely, the effects of repaglinide on the pharmacokinetics of drugs with only a narrow margin between effective and toxic concentrations, such as digoxin or theophylline, were determined. The studies reported here compared monotherapy with combined therapies in healthy volunteers. There were no significant differences between the pharmacokinetic parameters of repaglinide when given as monotherapy and when administered concurrently with cimetidine. Similarly, the coadministration of repaglinide and digoxin did not influence the pharmacokinetics of digoxin administered alone. When repaglinide was coadministered with theophylline, the only pharmacokinetic change was that the peak plasma theophylline concentration was slightly reduced. No direct drug‐drug interactions were found in these studies, suggesting that repaglinide may be coprescribed with cimetidine, digoxin, or theophylline at the dosage used for monotherapy.

Repaglinide Pharmacokinetics in Healthy & Chronic Liver Disease Subjects

Clinical Pharmacology & Therapeutics (1999) 65, 187–187; doi:

Disposition of One Dose of 14C-Repaglinide During Non-Labeled Repaglinide Multiple Dosing

Clinical Pharmacology & Therapeutics (1999) 65, 187–187; doi: