Steady-state plasma concentrations as a function of the absorption rate and dosing interval for drugs exhibiting concentration-dependent clearance: Consequences for phenytoin therapy

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Abstract
Model-dependent relationships describing the effects of absorption rate and dosing interval on steady-state phenytoin plasma concentrations are presented and discussed. Utilizing a range of operative Michaelis-Menten parameters that characterize phenytoin elimination via a single capacity-limited pathway, a situation assuming instantaneous absorption (case I) is compared with the situation in which continuous constant-rate absorption occurs (case II). The results of these comparisons demonstrate that average steady-state concentrations do not differ significantly between the two cases. Ratios (case I/case II) of areas under the curve during a steady-state dosing interval substantially deviating from unity are associated with high plasma clearances and clinically low phenytoin concentrations. When the same daily dose is maintained, but the dosing interval is altered (0.25, 0.33, 0.50, 1.0 day), little difference in the average steady-state levels is observed even when absorption is instantaneous. Differences between steady-state maximum and minimum concentrations increase with prolonged dosing intervals as well as faster absorbed phenytoin formulations, but for most patients these fluctuations are therapeutically insignificant. A dimensionless parameter, Q,which is a function of the individual patient's parameters and the dosing regimen, is introduced, and its relationship with steady-state phenytoin concentrations is discussed. Formulation-related differences in phenytoin dissolution rates that may result in significantly altered absorption rates should not affect average steady-state levels unless the extent of absorption is altered. More frequent dosing is not necessary to avoid increases in the average steady-state levels when rapidly absorbed phenytoin products are administered, but may be desirable if the required daily dose is high or the individual patient exhibits a narrow therapeutic range for this drug.