Nateglinide, a New Mealtime Glucose Regulator
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Clin Drug Invest 2000 Jun; 19 (6): 465-471 1173-2563/00/0006-0465/$20.00/0 © Adis International Limited. All rights reserved.
Nateglinide, a New Mealtime Glucose Regulator Lack of Pharmacokinetic Interaction with Digoxin in Healthy Volunteers Honghui Zhou,1 Yulia H. Walter,1 Harold Smith,2 Damayanthi Devineni1 and James F. McLeod1 1 Clinical Pharmacology Department, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA 2 Bioanalytics and Pharmacokinetics Department, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
Abstract
Objective: To investigate any possible pharmacokinetic interactions that may occur following the coadministration of nateglinide, a new mealtime glucose regulator, and digoxin. Design and Setting: This was a partially randomised, three-period, nonblind, crossover study performed at a single centre in healthy male and female volunteers aged 19 to 36 years. Methods: During treatment period 1, all study participants received nateglinide 120mg three times daily for 1 day. They were then randomised to two treatment sequences (n = 6 in each group) in periods 2 and 3, during which they received either a single dose of digoxin 1mg or the combination of nateglinide 120mg three times daily for 2 days plus a single dose of digoxin 1mg on the first day. Blood samples were collected and pharmacokinetic parameters derived. Safety variables measured included ECG parameters and blood pressure. Results: The concurrent administration of nateglinide and digoxin did not affect the pharmacokinetics of either drug. On the basis of cardiac and haemodynamic assessments, there was no evidence of pharmacodynamic interaction between digoxin and nateglinide. During the study, nateglinide was well tolerated and there were no serious adverse events or drug-related discontinuations in volunteers receiving nateglinide alone or in combination with digoxin. Conclusion: No adjustment of the dosage of either digoxin or nateglinide is necessary when the drugs are coadministered.
Patients with type 2 diabetes mellitus are at increased risk of developing congestive heart failure. Older patients with diabetes have been shown to have a 1.3-fold higher chance of developing congestive heart failure in comparison with their nondiabetic peers.[1]
Digoxin is the most commonly used cardiac glycoside for the management of congestive heart failure. Nevertheless, this drug has a narrow therapeutic index (target plasma concentration range 0.5 to 2 μg/L),[2] and recent reports suggest that the absorption of digoxin may be decreased via an
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unknown mechanism when coadministered with the antidiabetic agent acarbose.[3-5] When coadministered with atorvastatin, [6] inhibition of P-glycoprotein–mediated digoxin secretion into the intestinal lumen increases systemic digoxin concentrations. More commonly, plasma concentrations of digoxin are significantly increased when coadministered with drugs (e.g. verapamil[7] or quinidine[8]) that inhibit P-glycoprotein–mediated digoxin elimination by the kidney. It is the
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