Predictive Performance of the Winter-Tozer and Derivative Equations for Estimating Free Phenytoin Concentration

The Winter-Tozer equation for estimating free phenytoin concentration is biased and imprecise. Alternative predictive equations are available, but most remain unvalidated.

To assess the bias and precision of the Winter-Tozer equation and selected derivative equations in predicting free phenytoin concentration and to derive new equations with better predictive performance.

A retrospective chart review (for patients with samples drawn for free phenytoin concentration between September 2008 and September 2013) was conducted for 3 subpopulations (critical care, general medicine, neurology) in one hospital. Patients were included if older than 18 years with values for free phenytoin concentration available and were excluded if phenytoin was not at steady state or if they were undergoing hemodialysis or receiving enzyme inhibitors or inducers that would affect phenytoin clearance. The predictive performance measures used were mean prediction error (MPE), root mean square error, and Bland-Altman plots. Spearman rank correlation and multiple linear regression were performed with log-transformed data.

In total, 133 patients were included (70 men [53%]; mean age ± standard deviation 64 ± 19 years; serum creatinine 90.4 ± 64.0 µmol/L; albumin 26.4 ± 7.0 g/L). In the combined population, the Winter-Tozer equation (MPE 1.7 µmol/L, 95% confidence interval [CI] 1.5 to 1.9) and the Anderson equation (MPE 0.5 µmol/L, 95% CI 0.3 to 0.7) over-predicted free phenytoin concentration, whereas the first Kane equation tended to underpredict free phenytoin (MPE -0.2 µmol/L, 95% CI -0.4 to 0.0), and the second Kane equation significantly underpredicted free phenytoin (MPE -0.3 µmol/L, 95% CI -0.5 to -0.1). In each subpopulation, the Winter-Tozer equation overpredicted true concentration with greater bias and imprecision. All equations performed poorly in the critical care subpopulation. Only albumin (R (2) = 0.09) and total phenytoin concentration (R (2) = 0.53) were correlated with free phenytoin concentration. The equation derived by multiple linear regression exhibited significantly less bias and imprecision than the Winter-Tozer equation in the validation set (p < 0.05). A new, user-friendly equation, specific to the authors' patient population, was derived, which had an albumin coefficient of 0.275.

Relatively poor predictive performance of the Winter-Tozer and derivative equations calls for more precise and less biased equations. The novel equations presented here, which had better predictive performance for free phenytoin concentration and were based on a large sample of adult patients, should be further validated in other institutions.