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From the Department of Neurology and Neuroscience (Dr. Wilder), College of Medicine, University of Florida, Gainesville; MINCEP Epilepsy Care, Department of Neurology and College of Pharmacy (Dr. Leppik), University of Minnesota, Minneapolis; Department of Experimental and Clinical Pharmacology (Dr. Hietpas), College of Pharmacy, University of Minnesota, Minneapolis; and Department of Clinical Pharmacokinetics and Pharmacodynamics (Dr. Cook), Pfizer Global Research and Development, Ann Arbor, MI.
Address correspondence and reprint requests to Dr. B.J. Wilder, Professor Emeritus, Neurology and Neuroscience, University of Florida, 10530 NW 15th Place, Gainesville, FL 32606; e-mail: epilepsy{at}worldnet.att.net
Background:— Because of phenytoin’s narrow therapeutic index and nonlinear pharmacokinetics, food-induced alterations in absorption may markedly influence drug concentrations and, in turn, safety and effectiveness. Potential food-associated differences between 100-mg Mylan (Mylan Pharmaceuticals) extended-release phenytoin sodium capsules and Parke–Davis 100-mg Dilantin Kapseals were examined.
Methods:— A single-dose, two-way crossover study was conducted in 24 healthy subjects to determine the effect of a high-fat meal on the pharmacokinetics of both formulations. Pharmacokinetic parameters were estimated by noncompartmental methods. The impact of switching products on steady-state phenytoin concentrations was investigated through simulation using pharmacokinetic data previously obtained from 30 epileptic patients.
Results:— Based on AUC(0–
), bioavailability of the Mylan product administered with food was 13% lower than that observed with Dilantin Kapseals. Simulations of substituting the Mylan product for Dilantin suggested that the 13% decrease in bioavailability would result in a median 37% decrease (range 19 to 58%) in plasma phenytoin concentrations when the drug is given with food; in 46% of patients, phenytoin concentrations would likely fall below the therapeutic range of 10 to 20 mg/L. Simulations of substituting Dilantin for the Mylan product suggested that the 15% increase in bioavailability would result in a median 102% increase (range 24 to >150%) in plasma phenytoin concentrations, with 84% of patients having phenytoin concentrations above the therapeutic range.
Conclusions:— Results suggest that when taking phenytoin sodium with food, product switches may result in either side effects or loss of seizure control.
This article has been cited by other articles:
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  T. E Welty Pharmacy and Generic Substitution of Antiepileptic Drugs: Missing in Action? Ann. Pharmacother., June 1, 2007; 41(6): 1065 - 1068. [Abstract] [Full Text] [PDF]
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R. T. Burkhardt, I. E. Leppik, K. Blesi, S. Scott, S. R. Gapany, and J. C. Cloyd Lower phenytoin serum levels in persons switched from brand to generic phenytoin Neurology, October 26, 2004; 63(8): 1494 - 1496. [Abstract] [Full Text] [PDF]
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B. M. Davit, G. J. P. Singh, D. P. Conner, B.J. Wilder, J. C. Cloyd III, J. Cook, R. P. Lesser, and G. Krauss Effect of food on absorption of Dilantin Kapseals and Mylan extended phenytoin sodium capsules Neurology, February 26, 2002; 58(4): 666 - 667. [Full Text] [PDF]
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R. P. Lesser and G. Krauss Buy some today: Can generics be safely substituted for brand-name drugs? Neurology, August 28, 2001; 57(4): 571 - 573. [Full Text] [PDF]
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J. Cook, E. Randinitis, and B. J. Wilder Effect of food on the bioavailability of 100-mg Dilantin Kapseals Neurology, August 28, 2001; 57(4): 698 - 700. [Abstract] [Full Text] [PDF]
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