Characterization of unbound phenytoin concentrations in neurointensive care unit patients using a revised Winter-Tozer equation

Ann Pharmacother. 2013 May;47(5):628-36. doi: 10.1345/aph.1R651. Epub 2013 Apr 19.


Background: Prior studies examining the accuracy of the Winter-Tozer (WT) equation for correcting total phenytoin concentrations in critically ill patients have yielded conflicting results and are limited by small sample sizes and stringent exclusion criteria, which lessen external validity.

Objective: To determine whether the traditional WT equation is appropriate in correcting total phenytoin concentrations in a large sample of patients in a neurointensive care unit (NICU) and whether a new equation may be more predictive.

Methods: In a retrospective study, NICU patients with reports of a concurrent total and unbound phenytoin concentration and albumin level were analyzed. Two new predictive equations were generated using a revised WT equation and regression model of baseline and laboratory characteristics. Prediction error analysis using a 20% validation cohort was conducted on all 3 equations for comparison.

Results: A total of 140 adults were included for data analysis, with data on 80% used for derivation and 20% as validation of all equations. The mean unbound phenytoin concentration was 1.4 μg/mL, which represented a free fraction of 10%. Most samples were collected within 24 hours of NICU admission. Multivariate regression analysis demonstrated that albumin, total phenytoin concentration, sex, and creatinine clearance were predictive of measured unbound phenytoin concentrations. The traditional WT equation significantly underpredicted true unbound phenytoin concentrations, with 32.1% of patients having a prediction error of more than 50% in the validation cohort.

Conclusions: The traditional WT equation was significantly biased in underpredicting true unbound phenytoin concentrations in neurointensive care unit patients and should not be used in this setting. Two modified equations were more accurate and precise and should be considered for use when unbound phenytoin concentrations are not readily available in an NICU population.

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Algorithms*
  • Anticonvulsants / blood*
  • Anticonvulsants / pharmacokinetics
  • Body Weight
  • Creatinine / blood
  • Critical Illness*
  • Humans
  • Intensive Care Units*
  • Middle Aged
  • Phenytoin / blood*
  • Phenytoin / pharmacokinetics
  • Racial Groups
  • Retrospective Studies
  • Sex Factors


  • Anticonvulsants
  • Phenytoin
  • Creatinine