Abstracts

Rationale: Narrow therapeutic index (NTI) drugs are those where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions. To ensure safety, efficacy, and switchability of generic NTI drugs, FDA applies more stringent quality and bioequivalence (BE) standards in generic approval of NTI drugs. Phenytoin is an antiepileptic drug (AED) indicated for control of generalized tonic-clonic and complex partial seizures. While neurologists consider most AEDs as NTI drugs, there is no systemic evaluation on the NTI classification of individual AEDs. In this poster we present evidence to classify phenytoin as an NTI drug. Methods: We reviewed drug product labels, literature reports, and the innovator and generic phenytoin applications to collect information on the pharmacokinetics (PK), pharmacodynamics (PD), dose-response curves, and clinical practice of phenytoin and phenytoin sodium products on the US market. Five characteristics support NTI classification: 1) There is little separation between effective concentrations and concentrations associated with serious toxicity; 2) Sub-optimal doses or concentrations lead to severe therapeutic failure or toxicity; 3) It possesses low-to-moderate (i.e. no more than 30%) within-subject variability; 4) It is subject to therapeutic monitoring based on PK or PD measures; and 5) Doses are adjusted in small increments (less than 20%) in clinical practice. Results: The minimum effective concentration (C_eff,min) of phenytoin is generally reported to be 10 ug/mL while the minimum concentration of serious toxicity (C_tox,min) is 20 ug/mL. The ratio between C_tox,min and C_eff,min is 2. This value is comparable to that of the established NTI drugs such as warfarin and tacrolimus. Concentrations outside the therapeutic ranges either lead to loss of seizure control or result in central neural system damages as reflected by nystagmus, ataxia, dysarthria, or lethargy. Data submittetd to FDA shows that the approved phenytoin products have a mean residual variability (CV%) of 10.56% and 16.27% on AUC_t and C_max. The drugs are subject to routine therapeutic drug monitoring based on plasma phenytoin levels. The maintenance doses are usually between 3-6 mg/kg per day depending on patient characteristics, and dose adjustment is generally performed in small increments (30-100 mg/day) based on plasma phenytoin levels. Conclusions: Phenytoin demonstrates the five general characteristics of NTI drugs.