Relative Bioavailability of Two Different Phenytoin Preparations

Abstract

Relative bioavailability (RB) of two commercially available phenytoin preparations showed greater differences in absorption in children than in adults. 93 patients received one or more doses of one or two preparations. Serum assays were made at steady state. Age-matched groups were compared. In another cross-over study, 12 patients received two or more doses of each formulation until steady state levels were reached. 5 adult volunteers received single doses of each preparation, and multiple serum samples were assayed to define the peak blood concentration and area under the curve. To calculate RB, the value of V(max)/F was determined from plots of serum concentration (C) vs. C/dose (C/D). Bioavailability was greater in the preparation with the smaller crystal size and more rapid in vitro dissolution. Relative bioavailability increased with increasing age, suggesting an age-dependent effect on drug absorption.

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

“…As listed in Table IV, 28 studies reported DRBA attributed to age-related absorption (differences in absorption between pediatric and adult populations). Fifteen out of 28 studies reported multiple absorption-related risk factors (8,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), including alterations in GI transit time or motility (8,33,36,38,40,44), changes in GI fluid composition (37,40), and different levels of saturation for intestinal transporters/ metabolism (8,42). Moreover, 11 of the studies from the list of 28 reported factors are also related to the formulations used (32, 34-41, 43, 45), and 5 also related to the drug substance (8,33,38,40,44).…”

“…Fifteen out of 28 studies reported multiple absorption-related risk factors (8,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), including alterations in GI transit time or motility (8,33,36,38,40,44), changes in GI fluid composition (37,40), and different levels of saturation for intestinal transporters/ metabolism (8,42). Moreover, 11 of the studies from the list of 28 reported factors are also related to the formulations used (32, 34-41, 43, 45), and 5 also related to the drug substance (8,33,38,40,44). It should be noted that a BE study conducted as a crossover study would cancel out the age-related effects on clearance and highlight those effects that are related to formulation differences; however, due to the limited crossover BE studies conducted in pediatric populations, we summarized all the risk factors related to applying clinical study results from adults to pediatric populations.…”

“…This risk factor is associated with formulation changes that alter the rate of drug release (33,36,38,46). In previous studies conducted in adults, factors including bile flow, GI motility, bowel length, and food intake and composition were found to affect the absorption of certain cyclosporine formulations (38) and phenytoin (40). There is an interplay between formulation effects and GI transit, and if GI transit time limits drug absorption, differences in formulation may have impact on the absorption.…”

“…There is an interplay between formulation effects and GI transit, and if GI transit time limits drug absorption, differences in formulation may have impact on the absorption. Thus, the implications of these effects in adult studies may increase in pediatric populations (40).…”

“…Two studies were identified with DRBA attributed to differences in the volume of distribution (40,47): one specifically identified protein binding (40) and another study identified intracellular drug transport as risk factor for DRBA (47).…”