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To the Editor:
Wilder et al.1 conclude that, based on simulations, switching between Parke-Davis’ Dilantin Kapseals (Parke-Davis, Morris Plains, NJ) and Mylan’s phenytoin sodium extended capsules (Mylan Pharmaceuticals, Morgantown, WV) will alter steady-state phenytoin plasma concentrations causing either toxicity or lack of effect. We disagree with the assumptions underlying the simulations and with the authors’ conclusions.
Mylan’s product, approved in 1998, met the US Food and Drug Administration’s (FDA) requirements for bioequivalence (90% CI of generic/reference area under the curve [AUC] and Cmax geometric mean ratios between 0.8 and 1.25). For AUC, the 90% CI was 0.92 to 1.01 and the ratio of means was 0.97.2
In 1999, Parke-Davis, who manufactures Dilantin Kapseals, submitted to the FDA a study showing that Mylan’s product and Dilantin Kapseals were bioequivalent under fed conditions.2 The ratio of AUC means was 0.87. Wilder et al.1 used Vmax and Km estimations from an unrelated study3 to simulate effects on steady-state plasma concentrations. When the authors assumed either a 13% decrease or 15% increase in bioavailability, 46% and 84% of simulated values were outside the therapeutic range.
The authors’ simulations used a mean AUC ratio from one study and 30 Km and Vmax values from another study, published as an abstract. Mean data do not capture the extent of pharmacokinetic variability, the major factor contributing to frequency of subtherapeutic or toxic concentrations. Meaningful simulations should include appropriate levels of between- and within-subject variability and a sufficient number (at least 1,000) of subjects. The reader cannot evaluate how Km and Vmax were determined. Were doses high enough for accurate estimation, or were dose durations sufficient to achieve steady state?
The authors incorrectly conclude that small differences in phenytoin bioavailability following a 100-mg dose would greatly expand when higher doses are taken with …
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