An increase in serum phenytoin concentration by changes of dosage form: Case reports and its mechanism

Phenytoin (PHT) exhibits nonlinear pharmacokinetics in the therapeutic range. Therefore a slight increase in dose may lead to considerable elevation of the serum PHT level. Although its bioavailability is dependent on the formulation, bioequivalence is considered to be preserved between the three major formulations, of tablet, 97% fine granules, and 10% powder. However, we experienced many cases of increases serum PHT concentration after changes in formulation from 97% fine granules to 97/4% hospital-made fine granules, and from the latter to 10% powder. Retrospective analysis revealed that these alterations were accompanied by 55% and 16% increases in the serum concentration-to-dose ratio of PHT, respectively. We investigated the factors of this increase by analyzing the weight of remaining powder in a package and the PHT content of each formulation. Each package of PHT formulation prepared with 97% fine granules and 10% powder was unsealed, and the contents were weighed to calculate the rate of recovery. The rate of ingestion was estimated by correcting the rate of recovery by PHT strength (i. e., 1.0 for 10% powder and 0.97 for fine granules). The rates of recovery and ingestion for 10% powder were 13% and 16% higher than those for 97% fine granules, respectively (p<0.01). In conclusion, Changing the PHT formulation from 97% fine granules to 10% powder may lead to a considerable increase in the serum PHT concentration and possibly induce PHT toxicity.