Probabilistic Approach to the Establishment of Maximal Content Limits of Impurities in Drug Formulations: The Case of Parenteral Diphenylhydantoic Acid

Diphenylhydantoic acid (DPHA) is a degradation product in parenteral formulations of the anticonvulsant phenytoin and the prodrug fosphenytoin. DPHA has also been reported to be a minor metabolite of phenytoin. Levels found in the urine of various species, including humans, after oral or intravenous (iv) phenytoin ranged from undetected to a few percent of administered dose. In the present analysis, the toxicologic profile of DPHA was integrated with exposure data in order to characterize its safety under recommended clinical regimens of fosphenytoin administration. In preclinical safety studies, DPHA was without effect in the Ames assay and at concentrations up to 3000 μg/plate in the presence or absence of metabolic activation, and in thein vitromicronucleus test with acute and 2-week repeated dose studies in Wistar rats at iv doses up to 15 mg/kg. In 4-week studies conducted in rats and dogs receiving fosphenytoin containing DPHA levels up to 1.1%, and in anin vitrostructural chromosome aberration test with DPHA levels up to 2.0%, all findings were consistent with known effects of phenytoin (such as CNS signs and increased liver weight), and none were attributed to DPHA. Reports in the literature indicate that in murinein vivoandin vitromodels, DPHA has much lower potential for reproductive toxicity than phenytoin. A no-observed-effect level (NOEL) of 15 mg/kg established from the 2-week study in rats was used with probabilistic techniques to estimate tolerable daily doses (TDDs) of DPHA. In this approach, interspecies correction was performed by allometrically scaling the NOEL based on a distributional power of body weight while intraindividual variability was accounted for by selecting the lower percentiles of the population-based distribution of TDDs. The results indicate that a DPHA content limit of 3.0% in an administered dose of fosphenytoin is unlikely to cause adverse effects in patients.