A Novel Correction Equation Avoids High-Magnitude Errors in Interpreting Therapeutic Drug Monitoring of Phenytoin Among Critically Ill Patients

Abstract

Background: Phenytoin has a narrow therapeutic index and the potential of under-treatment or toxicity. Available equations are used to correct for the impact of hypoalbuminemia on unbound (free) phenytoin levels. The authors aimed to determine the accuracy of equations used to estimate free phenytoin in hospitalized patients and assess the impact of using additional clinical data. Methods: Concurrently measured total and free phenytoin levels in hospitalized patients (2014–2018) were retrospectively evaluated, excluding those from patients on renal replacement therapy and valproic acid. Differences between actual and estimated free phenytoin levels by the original (Original WTZ), Anderson-modified, and Kane-modified Winter–Tozer equations were assessed using Pearson correlations and Bland–Altman analysis. Thereafter, a population-derived formula was developed and validated in a testing cohort. Results: In the 4-year training cohort (n = 81), the Original WTZ equation had the smallest mean difference of all equations. A higher mean difference [−0.362 mcg/mL (95% CI −0.585 to −0.138) vs. −0.054 mcg/mL (95% CI −0.186 to 0.078)] was observed in intensive care unit (ICU) patients compared with non-ICU patients. A cross-validated multivariable model improved the accuracy of free phenytoin estimation in ICU and non-ICU patients, even in the separate testing cohort (n = 52) with respective mean differences of −0.322 mcg/mL (95% CI −0.545 to −0.098) and −0.025 mcg/mL (95% CI −0.379 to 0.329) and was superior to the Original WTZ [mean difference −0.858 mcg/mL (95% CI −1.069 to −0.647) vs. −0.106 mcg/mL (95% CI −0.362 to 0.151), respectively]. Conclusions: Free phenytoin levels in hospitalized patients cannot be accurately determined using available estimation equations, particularly in critically ill patients. Combining ICU status and other available clinical data can improve therapeutic drug monitoring and prevent high-magnitude errors, particularly when free phenytoin assays are not readily available.

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

“…Moreover, the number of samples considered was too small to give a statistical validation of the predictive model. A recent work by Barra et al reached the same conclusions, showing that the Sheiner–Tozer, as well as equation derived from it, underestimated the real levels of free PHT in patients admitted to ICUs [ 90 ]. This study also underlined that the error in the quantitation of free drug was one order of magnitude greater in critically ill patients than in those admitted to a non-critical unit.…”

Therapeutic drug monitoring of phenytoin and valproic acid in critically ill patients at Windhoek Central Hospital, Namibia

“…31 Furthermore, recent investigations on the predictive performance of these equations led to the conclusion that more complex, multivariate predictive equations may be required, which, in addition to the total drug plasma concentration and serum albumin level, considering the ICU status of the patient, age, and blood urea nitrogen level. 30,28 Therapeutic drug monitoring of phenytoin and valproic acid should be based on unbound drug concentrations. The best way to monitor the unbound drug concentration would be by measuring it directly in ultrafiltrate obtained from serum to ensure that the accurate concentration of the free drug is determined and used to inform dosage adjustment.…”

“…5 , 18 , 19 , 20 , 21 , 22 Unfortunately, these equations are not very accurate and may underestimate the unbound plasma concentrations of phenytoin and valproic acid in critically ill patients. 25 , 26 , 27 , 28 , 29 , 30 In addition, although the therapeutic plasma range for unbound phenytoin is relatively established (1 μg/mL – 2 μg/mL), various therapeutic ranges for the unbound plasma concentration of valproic acid have been proposed in the literature. However, more research is needed to determine the optimal unbound plasma concentration range for this anticonvulsant.…”

“… 31 Furthermore, recent investigations on the predictive performance of these equations led to the conclusion that more complex, multivariate predictive equations may be required, which, in addition to the total drug plasma concentration and serum albumin level, considering the ICU status of the patient, age, and blood urea nitrogen level. 30 , 28 …”

Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations

“…19 , 20 Despite being decades old, the accuracy of these equations has been questioned by recent researchers. 21 – 23 In this situation, the direct-measurement of free phenytoin concentration in serum, especially in the critically ill could be essential. 24 …”