Total Phenytoin Concentrations Research Articles

On-Cell Stability for Therapeutic Drug Monitoring

Abstract Introduction A common problem in many clinical laboratories and outpatient clinics is processing specimens rapidly to comply with specimen stability criteria. Labs receive thousands of samples a day and may face challenges with staffing, equipment malfunction, or workflow, which can prevent immediate processing of samples. Currently, for therapeutic drug monitoring, the lab is required to centrifuge specimens and remove the serum/plasma from cells within 2-hours (CLSI-GP44-A4). Many of these drugs are monitored in the outpatient setting, which may require longer transportation times to get specimens from the collection location to the laboratory. This creates challenges for the lab in processing samples within 2-hours and may result in unnecessary rejection of otherwise acceptable specimens. Not all clinical sites have the staffing or space to process the specimens on site. Our objective was to determine if the on-cell stability of therapeutic drugs can be extended to beyond two hours. Methods We performed spiking studies to determine the on-cell stability of phenytoin in whole blood that was collected from healthy donors in barrier-free red top tubes. Phenytoin was spiked into the whole blood at a final concentration of about 10 (therapeutic) or 40 (toxic) µg/mL. The spiked whole blood samples were mixed by inverting six times and then were left at ambient temperature for 30 minutes, 2-, 4-, 6-, or 12-hours, after which they were centrifuged, and the serum was removed for analysis of total phenytoin concentration on the Abbott Architect and free and total phenytoin on the Beckman AU (n=3 per time point and concentration). In vivo studies are ongoing for an extended list of therapeutic drugs, in which two extra red top tubes are collected from patients being monitored for phenytoin, valproic acid, digoxin, vancomycin, lithium, or carbamazepine therapy. The two study tubes are kept at ambient temperature for 6- or 12-hours after collection before being centrifuged and separated from cells. The 6- and 12-hour drug concentrations were compared to the patient’s standard of care tube that was processed within 2-hours, after clotting for 30 minutes. Results Spiking studies demonstrated phenytoin was stable on cells for at least 12-hours at both 10 and 40 µg/mL. The percent total phenytoin remaining at 12-hours relative to the 30-minute control was 104 ± 2% at 10 µg/mL and 99 ± 16% at 40 µg/mL. Furthermore, the fraction of free phenytoin did not change over the 12 hours (10 µg/mL: 8 ± 1% free; 40 µg/mL: 10 ± 1% free). Our preliminary in vivo studies have shown no change in vancomycin or lithium concentration in samples processed 6- and 12-hours post-collection. Conclusion We have demonstrated that phenytoin, vancomycin, and lithium collected in red-top tubes are stable on cells at ambient temperature for at least 12-hours.

Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients

IntroductionWe aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (CPHT). MethodsWe retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two CPHT measurements were analyzed, one 2–4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate CPHT. ResultsThe present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2–27.2) mg/kg. The CPHT was 13.4 (8.6–18.9) μg/mL 2–4 h after the loading dose. The CPHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7–14.2) and 5.8 (3.7–10.0) μg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the CPHT on day 8 was estimated to be 5.74 (2.6–15.4) μg/mL at 5 mg/kg and 13.9 (5.7–31.0) μg/mL at 7.5 mg/kg. ConclusionsIn pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5–7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring CPHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.

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

BackgroundIn critically ill patients with low albumin, dose individualization of phenytoin is a challenge. The currently used Sheiner–Tozer equation does not accurately predict the free phenytoin concentration in serum and can result in incorrect dose modifications. The best measure to advocate in these patients is the direct-measurement of free phenytoin concentration.Aims and objectivesPhenytoin exhibits complex pharmacokinetics, requiring careful therapeutic drug monitoring. This study aimed to compare the accuracy of the established Sheiner–Tozer calculation method against the direct-measurement of free phenytoin concentration in serum by high performance liquid chromatography in critically ill patients with low albumin.Materials and methodsBlood specimens for direct-measurement of both total and free phenytoin concentration were obtained from 57 patients with hypoalbuminemia monitored in the intensive care unit.ResultsThe median [inter-quartile range (IQR)] for Sheiner–Tozer equation calculated total phenytoin concentration and direct-measured total was 17.14 (10.63–24.53) and 9.82 (6.02–13.85) μg mL−1, respectively. Approximately 53 and 5% of patients were found to be subtherapeutic and supratherapeutic for direct-measured total phenytoin concentrations, respectively. In contrast, on applying the Sheiner–Tozer calculation, 23 and 40% had subtherapeutic and supratherapeutic concentrations, respectively, for total phenytoin concentration. The median (IQR) for direct-measured, routine and Sheiner–Tozer equation calculated free phenytoin concentration were 1.92 (1.06–2.76), 0.98 (0.60–1.39), and 1.71 (1.06–2.45) μg mL−1, respectively. Only 45.7% of patients were in agreement with respect to the therapeutic category when direct-measured free was compared against routine calculation free.ConclusionIn patients with low albumin, free phenytoin concentration based on the Sheiner–Tozer corrected equation accurately classified patients based on their therapeutic category of free phenytoin in 73.7% of patients. Hence, for individualization of phenytoin dosage in critically ill patients with low albumin, we recommend direct-measurement of free phenytoin concentration.How to cite this articleWilfred PM, Mathew S, Chacko B, Prabha R, Mathew BS. Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations. Indian J Crit Care Med 2022;26(6):682–687.

Monitoring for valproate and phenytoin toxicity in hypoalbuminaemia: A retrospective cohort study.

Equations to calculate albumin-adjusted total concentrations have been validated to correlate with measured free concentrations for both phenytoin and valproate, but there is a lack of data to assess correlation with clinical outcomes. We aimed to assess the association of hypoalbuminaemia and albumin-adjusted total concentrations with concentration-dependent toxicity for phenytoin and valproate and review the impact on management decisions following concentration monitoring in hypoalbuminaemia. Patients undergoing concentration monitoring for phenytoin or valproate between January and December 2018 were included. Patients were identified using a centralised laboratory database with data extracted from medical records. Total phenytoin concentrations were measured for 144 patients, with hypoalbuminaemia (≤30 g L-1 ) recorded in 59 (41%) patients. Albumin-adjusted phenytoin concentration >20 mg L-1 was associated with increased neurological adverse effects (77% vs. 43%, P < .001). On logistic regression, higher albumin-adjusted phenytoin concentration was an independent risk factor for neurotoxicity (OR 1.06, 95% CI 1.01-1.12, P = .011). Total valproate concentrations were measured for 383 patients, with hypoalbuminaemia (≤30 g L-1 ) noted in 53 (14%) patients. For the valproate cohort, hypoalbuminaemia (42% vs. 28%, P = .039) and albumin-adjusted valproate concentration >100 mg L-1 (49% vs. 23%, P < .001) were both associated with increased neurotoxicity. On multiple logistic-regression, valproate daily dose (aOR = 1.01, 95% CI 1.00-1.02, P = .006) and albumin-adjusted valproate concentration (aOR 1.01, 95% CI 1.00-1.02, P = .033) were independent risk factors for neurotoxicity after accounting for confounders. While measuring free drug concentrations in hypoalbuminaemia would be ideal, the adjustment equations can help identify vulnerable patients needing further assessment of potential concentration-dependent toxicity.

Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction.

Several methods are available to predict unbound (free) phenytoin concentrations in patients with hypoalbuminemia; however, predictive methods have not been evaluated in patients with concurrent hypoalbuminemia and kidney dysfunction or in patients with mild to moderate (estimated glomerular filtration rate [eGFR] 30-90 ml/min/1.73 m2 ) kidney dysfunction alone. Thus the objective was to evaluate the accuracy and precision of predictive methods to estimate free phenytoin concentrations in patients with varying albumin concentrations and/or kidney dysfunction. Retrospective chart review. Large academic medical center. A total of 344 patients with free and total phenytoin, albumin, and serum creatinine concentrations obtained between November 2012 and May 2017. Free phenytoin concentrations were estimated in patients without kidney dysfunction using the Winter-Tozer, Anderson, Kane, and Cheng equations. For the analysis in patients with eGFR lower than 90ml/min/1.73m2 , free phenytoin concentrations were estimated using the Shiner-Tozer derivation with adjusted affinity coefficients (C=0.15, 0.20, 0.25, and 0.30). For both analyses, accuracy of predictive methods was evaluated by P20, the proportion of estimations within 20% of the measured free phenytoin concentration. In 158 patients with normal kidney function/normal albumin concentrations, 73 with normal kidney function/hypoalbuminemia, or 47 with mild kidney dysfunction/normal albumin concentrations, the Anderson method had the highest accuracy (86%, 82%, and 92%, respectively) and highest precision compared with the other methods. In 47 patients with normal albumin concentrations and mild kidney dysfunction or 13 with moderate kidney dysfunction, the free fraction was unchanged, and total phenytoin concentrations accurately reflected free concentrations. In 17 patients with hypoalbuminemia and mild or 17 with moderate kidney dysfunction, the Winter-Tozer (67% and 50%, respectively) and the Anderson (56% and 67%, respectively) methods had the highest accuracy compared with other methods with significantly lower accuracy compared with patients with normal kidney function. In the 14 patients with severe kidney dysfunction and hypoalbuminemia, none of the coefficients had a P20 accuracy greater than 45%. In patients with normal albumin concentrations, with or without mild or moderate kidney dysfunction and not receiving a protein-binding displacer, the free fraction of phenytoin is unchanged, and it is not necessary to measure a free phenytoin concentration. Free phenytoin concentrations should be measured directly in patients with hypoalbuminemia and kidney dysfunction.

Impact of Obesity on Fosphenytoin Volume of Distribution in Pediatric Patients.

The impact of body habitus on fosphenytoin pharmacokinetics is poorly understood in pediatric patients. This retrospective, single-center review examined differences in fosphenytoin volume of distribution (VD) between children with normal and obese body habitus. From 2013 to 2015, patients 2 to 18 years of age who received a loading dose of fosphenytoin were identified. Thirty-seven patients met inclusion criteria. Mean total serum phenytoin concentration was 25.3 ± 6.5 μg/mL in the nonobese group and 29.5 ± 7.6 μg/mL in the obese group ( P = .09). VD was not significantly different between obese and nonobese groups, 0.92 ± 0.26 L/kg and 0.97 ± 0.48 L/kg ( P = .76), respectively. In contrast to adult studies, these data suggest that fosphenytoin dose adjustments for obese children may be unnecessary.

Prediction Accuracy of Winter-Tozer Equations to Estimate Free Phenytoin Concentrations in Non-Critically Ill Hospitalized Patients.

To assess the accuracy of the standard and revised Winter-Tozer (WT) equations of predicting free phenytoin (PHT) concentrations in non-critically ill, hospitalized patients. Retrospective chart review. Single-center, large urban community hospital. Patients with free PHT levels obtained during the study period were reviewed. Thirty-nine non-critically ill, hospitalized adults met the inclusion criteria. The study population consisted of 77% African-Americans and 77% individuals 65 years of age and older. PHT concentrations were measured at ambient temperature. Predicted free PHT concentrations were estimated as 10% of normalized total PHT concentrations using standard or revised WT equations in two groups of patients with hypoalbuminemia and end-stage renal disease (ESRD). Correlation between measured versus predicted free PHT concentrations in patients with hypoalbuminemia or ESRD. Strong positive correlations were identified between measured and predicted free PHT concentrations for 27 patients with hypoalbuminemia (r [the Pearson correlation coefficient] = 0.96; P < 0.001) and 12 patients with ESRD (r = 0.95; P < 0.001). This study population represented a largely understudied population in this research area. Use of traditional and revised WT equations in primarily elderly, non-critically ill African-American populations can be considered to accurately predict PHT levels in populations with altered PHT albumin binding resulting from hypoalbuminemia or ESRD and settings where free PHT levels are not readily obtainable.

Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation.

The Winter-Tozer (WT) equation has been shown to reliably predict free phenytoin levels in healthy patients. In patients with end-stage renal disease (ESRD), phenytoin-albumin binding is altered and, thus, affects interpretation of total serum levels. Although an ESRD WT equation was historically proposed for this population, there is a lack of data evaluating its accuracy. The objective of this study was to determine the accuracy of the ESRD WT equation in predicting free serum phenytoin concentration in patients with ESRD on hemodialysis (HD). A retrospective analysis of adult patients with ESRD on HD and concurrent free and total phenytoin concentrations was conducted. Each patient's true free phenytoin concentration was compared with a calculated value using the ESRD WT equation and a revised version of the ESRD WT equation. A total of 21 patients were included for analysis. The ESRD WT equation produced a percentage error of 75% and a root mean square error of 1.76 µg/mL. Additionally, 67% of the samples had an error >50% when using the ESRD WT equation. A revised equation was found to have high predictive accuracy, with only 5% of the samples demonstrating >50% error. The ESRD WT equation was not accurate in predicting free phenytoin concentration in patients with ESRD on HD. A revised ESRD WT equation was found to be significantly more accurate. Given the small study sample, further studies are required to fully evaluate the clinical utility of the revised ESRD WT equation.

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.

A Comprehensive Review on the Predictive Performance of the Sheiner-Tozer and Derivative Equations for the Correction of Phenytoin Concentrations

In settings where free phenytoin concentrations are not available, the Sheiner-Tozer equation-Corrected total phenytoin concentration = Observed total phenytoin concentration/[(0.2 × Albumin) + 0.1]; phenytoin in µg/mL, albumin in g/dL-and its derivative equations are commonly used to correct for altered phenytoin binding to albumin. The objective of this article was to provide a comprehensive and updated review on the predictive performance of these equations in various patient populations. A literature search of PubMed, EMBASE, and Google Scholar was conducted using combinations of the following terms: Sheiner-Tozer, Winter-Tozer, phenytoin, predictive equation, precision, bias, free fraction. All English-language articles up to November 2015 (excluding abstracts) were evaluated. This review shows the Sheiner-Tozer equation to be biased and imprecise in various critical care, head trauma, and general neurology patient populations. Factors contributing to bias and imprecision include the following: albumin concentration, free phenytoin assay temperature, experimental conditions (eg, timing of concentration sampling, steady-state dosing conditions), renal function, age, concomitant medications, and patient type. Although derivative equations using varying albumin coefficients have improved accuracy (without much improvement in precision) in intensive care and elderly patients, these equations still require further validation. Further experiments are also needed to yield derivative equations with good predictive performance in all populations as well as to validate the equations' impact on actual patient efficacy and toxicity outcomes. More complex, multivariate predictive equations may be required to capture all variables that can potentially affect phenytoin pharmacokinetics and clinical therapeutic outcomes.

Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients.

Phenytoin is a common medication for seizure treatment and prophylaxis in the intensive care unit (ICU). The clinical utility of the Sheiner-Tozer equation for adjusting total phenytoin levels for hypoalbuminemia remains controversial. The purpose of this study was to evaluate the correlation of this formula in predicting phenytoin serum concentrations. A retrospective cohort study was conducted in the adult ICU between January 1, 2010, and June 21, 2013. Patients meeting the following study criteria were included: age ≥18 years, admission to the ICU, simultaneously drawn total and free serum phenytoin concentrations with albumin ≤48 hours of phenytoin draws. Study end points were the correlation as well as the level of agreement in the interpretation of the free and adjusted phenytoin concentrations using the Sheiner-Tozer formula in critically ill patients with hypoalbuminemia. A total of 238 patients were analyzed. Mean adjusted total phenytoin and free levels were 16.1 ± 8.1 and 1.5 ± 0.8 µg/mL, respectively (r = 0.817; P < 0.001). Absolute agreement with level interpretation between adjusted total phenytoin and free levels was 77% (κ = 0.633; P < 0.001). Adjusted phenytoin serum concentrations more frequently overestimated the free level. There is a significant correlation between free and adjusted total phenytoin levels using the Sheiner-Tozer equation in critically ill patients. However, disagreement was noted with interpretation, primarily because of the adjusted concentration overestimating the free level. This imprecision may lead to inaccurate decision making regarding the management of phenytoin in this patient population. Thus, free phenytoin levels should be utilized.

Canine status epilepticus treated with fosphenytoin: A proof of principle study.

There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available to treat status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs, with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people. A randomized clinical trial was performed for dogs with CSE. Dogs who presented during a seizure or who had additional seizures after enrolling received intravenous (i.v.) benzodiazepine (BZD) followed immediately by intravenous infusion of 15 mg/kg phenytoin equivalent (PE) of fosphenytoin (FOS) or saline placebo (PBO). If seizures continued, additional AEDs were administered per the standard of care for veterinary patients. Total and unbound plasma phenytoin (PHT) concentrations were measured. Consent was obtained for 50 dogs with CSE. Thirty-one had additional motor seizures and were randomized to the study intervention (22 FOS and 9 PBO). There was a statistically significant difference in the 12 h responder rate, with 63% in the FOS group versus 22% in the placebo group (p = 0.043) having no further seizures. The unbound PHT concentrations at 30 and 60 min were within the therapeutic concentrations for people (1-2 μg/ml) with the exception of one dog. There was mild vomiting in 36% of the FOS group (7/22) within 20 min of FOS administration and none of the placebo group (0/9) (p = 0.064). This proof of concept study provides the first evidence that FOS is tolerated and effective in canine SE at PHT concentrations clinically relevant for human SE. Furthermore, naturally occurring CSE can be utilized as a translational platform for future studies of novel SE compounds.

G335(P) Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading dose

AimPhenytoin’s loading dose for refractory tonic-clonic seizures in children was changed from 18 mg/kg to 20 mg/kg in January 2011 to reduce the theoretical risk of miscalculation. Phenytoin has complex...

Phenytoin Loading Doses in Adult Critical Care Patients: Does Current Practice Achieve Adequate Drug Levels?

Phenytoin is regularly employed in the critically ill for prophylaxis against or treatment of seizure disorders. No prior studies have examined current dosing practices in an Australasian intensive care unit (ICU) setting. The aims of this study were to: a) describe the adequacy of contemporary dosing in respect to free and total serum phenytoin concentrations; b) identify factors associated with therapeutic drug concentrations; and c) examine the accuracy of predictive equations that estimate free concentrations in this setting. All patients receiving a loading dose of phenytoin in a tertiary-level ICU were eligible for enrolment; 53 patients were enrolled in the study. Serum samples to determine free and total phenytoin concentrations (measured by high performance liquid chromatography) were then drawn prior to the following dose. Free concentrations below the recommended target (<1 mg/l) were considered as suboptimal. The most common indication for phenytoin loading was traumatic brain injury (49%) and the mean administered dose was 14.5 (3.66) mg/kg. Twenty-six patients (49%) had suboptimal trough free concentrations, although this subgroup was significantly heavier and therefore received a lower per kilogram dose (12.8 [3.1] vs 16.3 [3.4] mg/kg, P=0.001). In multivariate analysis, larger weight adjusted doses (P=0.018), higher albumin concentration (P=0.034) and receiving phenytoin for an indication other than seizure (P=0.035), were associated with a greater likelihood of adequate concentrations. In conclusion, phenytoin dosing remains complex in critically ill patients, although lower per kilogram loading doses are strongly associated with free concentrations below the desired target.

Characterization of Unbound Phenytoin Concentrations in Neurointensive Care Unit Patients Using a Revised Winter-Tozer Equation

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. 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. 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. 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. 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.

Total Phenytoin concentration is not well correlated with active free drug in critically-ill head trauma patients.

Objective:Phenytoin is an antiepileptic drug used widely for prophylaxis and treatment of seizure after neurotrauma. Phenytoin has a complex pharmacokinetics and monitoring of its serum concentrations is recommended during treatment. Total phenytoin concentration is routinely measured for monitoring of therapy. In this study, we evaluated the correlation between phenytoin total and free concentrations in neurotrauma critically-ill patients to determine whether the phenytoin total concentration is a reliable predictor of free drug, which is responsible for the therapeutic effects.Methods:A total of 40 adult head trauma patients evaluated for free (unbound) and total serum phenytoin concentrations. Patients were divided into two groups. Group A consists of 20 unconscious patients with severe head injury under mechanical ventilation and Group B consists of 20 conscious self-ventilated patients. Correlation and agreement between total and free phenytoin plasma concentrations were analyzed.Findings:Pearson correlation analysis and Bland-Altman test showed weak to moderate correlation (r = 0.528) and poor agreement between free and total phenytoin concentrations in patients with severe trauma and higher Acute Physiology And Chronic Health Evaluation II (APACHE II) scores (Group A) and good correlation (r = 0.817) and moderate agreement in patients with mild to moderate trauma and lower APACHE II scores (Group B).Conclusion:Our results indicated that total phenytoin serum concentration is not a reliable therapeutic goal for drug monitoring in severely-ill head trauma patients even in the absence of hypoalbuminemia, renal and hepatic failure. It seems justifiable to measure free phenytoin concentration in all severely ill neurotrauma patients.

Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers

PurposeWe performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.MethodsWe used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL.ResultsWe used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.ConclusionsThe pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.

Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

BackgroundTherapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. This is most commonly accomplished by measurement of total phenytoin plasma concentrations. However, total phenytoin levels can be misleading in patients with factors such as low plasma albumin that alter the free (unbound) concentrations of phenytoin. Direct measurement of free phenytoin concentrations in plasma is more costly and time-consuming than determination of total phenytoin concentrations. An alternative to direct measurement of free phenytoin concentrations is use of the Sheiner-Tozer equation to calculate an adjusted phenytoin that corrects for the plasma albumin concentration. Innovative medical informatics tools to identify patients who would benefit from adjusted phenytoin calculations or from laboratory measurement of free phenytoin are needed to improve safety and efficacy of phenytoin pharmacotherapy. The electronic medical record for an academic medical center was searched for the time period from August 1, 1996 to November 30, 2010 for patients who had total phenytoin and free phenytoin determined on the same blood draw, and also a plasma albumin measurement within 7 days of the phenytoin measurements. The measured free phenytoin plasma concentration was used as the gold standard.ResultsIn this study, the standard Sheiner-Tozer formula for calculating an estimated (adjusted) phenytoin level more frequently underestimates than overestimates the measured free phenytoin relative to the respective therapeutic ranges. Adjusted phenytoin concentrations provided superior classification of patients than total phenytoin measurements, particularly at low albumin concentrations. Albumin plasma concentrations up to 7 days prior to total phenytoin measurements can be used for adjusted phenytoin concentrations.ConclusionsThe results suggest that a measured free phenytoin should be obtained where possible to guide phenytoin dosing. If this is not feasible, then an adjusted phenytoin can supplement a total phenytoin concentration, particularly for patients with low plasma albumin.

Influence of CYP2C9 Genetic Polymorphism and Undernourishment on Plasma-Free Phenytoin Concentrations in Epileptic Patients

The objective of this study was to study the effect of CYP2C9 genetic polymorphism and undernourishment on free phenytoin concentrations in epileptic patients. The study was done in 70 patients who were taking phenytoin therapy for the treatment of epileptic seizures. Genotyping of CYP2C9 (*2 and *3) was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Bound and free plasma phenytoin was separated using equilibrium dialysis technique. Total and free phenytoin concentrations were measured by the reverse-phase high-performance liquid chromatography method. Patients were broadly classified into well-nourished and undernourished and further subclassified by CYP2C9 genotypes. In well-nourished groups (G1 to G3 group), free phenytoin concentrations were significantly higher in the heterozygous poor metabolizer of CYP2C9 genotype (G2) group (3.1 ± 0.62 μg/mL) and homozygous poor metabolizer of CYP2C9 genotype (G3) group (4.3 ± 1.76 μg/mL) when compared with patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/mL). Similarly, in undernourished patient groups (G4-G6 group), free phenytoin concentrations were significantly higher in the wild-type CYP2C9 (G4) group (2.5 ± 0.52 μg/mL), heterozygous poor metabolizer of CYP2C9 genotype (G5) group (4.3 ± 1.76 μg/mL), and homozygous poor metabolizer of CYP2C9 genotype (G6) group (8.2 ± 1.08 μg/mL) when compared with well-nourished patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/mL). The percentage increase in free phenytoin concentration by undernourishment, CYP2C9 allelic variants, and undernourishment cum CYP2C9 allelic variants were 127%, 290%, and 472%, respectively, compared with well-nourished patients with the wild-type CYP2C9 genotype (G1) group. The contribution of undernourishment and genetic factors (CYP2C9 allelic variant) for developing phenytoin toxicity was calculated to have an odds ratio of 37.3 (P < 0.0001). Undernourishment and variant CYP2C9 alleles elevate free phenytoin concentrations individually and in combination show additive effects.

Differences between the Measured and Calculated Free Serum Phenytoin Concentrations in Epileptic Patients

PurposeThe pharmacokinetics of phenytoin is complicated by genetic and environmental differences. It is, therefore, important to monitor the serum concentrations in patients who receive phenytoin. Because most of the phenytoin in serum is bound to proteins, the level of serum albumin influences the amount of free phenytoin.Materials and MethodsWe compared the measured and calculated free phenytoin levels in epileptic patients who were taking phenytoin monotherapy, using the Sheiner-Tozer equation. A total of 49 patients (30 men and 19 women; age range, 15 - 87 years) were included in the study and their trough serum phenytoin and albumin concentrations were analyzed.ResultsThe linear correlation between free and total phenytoin concentrations was moderate (r = 0.822, p < 0.001). The mean difference between measured and calculated free phenytoin was large (0.65 ± 0.88 µg/mL; 95% confidence interval (CI), -1.11 to 2.41). After dividing the patients into groups by albumin concentration, hypoalbuminemic patients (< 3.5 g/dL) more often had a greater percent difference (≥ 20%) than observed in the normoalbuminemic (≥ 3.5 g/dL) group.ConclusionIn hypoalbuminemic patients, the measurement of free phenytoin level is necessary to properly evaluate the phenytoin level than that calculated from total phenytoin level.