Total Phenytoin Research Articles

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.

Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus.

Canine status epilepticus (CSE) has potential as a translational platform to evaluate the safety and efficacy of novel compounds and inform human status epilepticus trials. The aim of this study was to determine the intravenous dose of fosphenytoin (FOS) needed for dogs in a CSE clinical trial to attain phenytoin (PHT) concentrations similar to those used for human status epilepticus and monitor PHT concentrations. Four healthy dogs were used to characterize PHT pharmacokinetics. Each received either 15 mg/kg or 25 mg/kg of PHT equivalent intravenously. Blood samples were collected and FOS (total) and derived PHT (total and unbound) plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Noncompartmental pharmacokinetics (PK) parameter values were determined and compartmental PK modeling and simulations were used to select the dose for the clinical trial with a target goal of 1-2 μg/ml unbound PHT at 30-60 min postinfusion. Predicted total and unbound PHT concentrations were compared with concentrations in blood collected from dogs treated for CSE in the clinical trial. Initial estimates suggested that a loading dose of 25 mg/kg would attain unbound concentrations of 1-2 μg/ml; however, this dose produced concentrations above 3-6 μg/ml, which resulted in clinically significant toxicity. A two-compartment model best fit the PHT concentration data with alpha-phase half-life of 2-5 min and elimination half-life of ~5 h. Based on the simulations, a dose of 15 mg/kg was selected and used in the clinical trial and 15 of 16 dogs randomized to the treatment arm had PHT plasma concentrations within the goal range. This study demonstrates that characterization of pharmacokinetics in a small number of dogs is useful in determining dosage regimens designed to attain targeted concentrations in clinical trials. Using this approach, we were able to determine a safe and effective dose of FOS for a clinical trial of CSE.

Phenytoin-Induced Purple Glove Syndrome: A Case Report and Review of the Literature.

To present a case report and literature review of phenytoin-induced purple glove syndrome (PGS). A 54-year-old African American male presented to our hospital's emergency department (ED) following a seizure episode, cardiac arrest, and loss of consciousness. On arrival to the ED, the patient's total phenytoin level was subtherapeutic at 4.1 mcg/mL and his corrected total phenytoin level was subtherapeutic at 5.1 mcg/mL. In the ED, the patient received a loading dose of intravenous (IV) phenytoin 1,000 mg once via the left cephalic vein, at a rate of 50 mg/min, and was admitted to the medicine service. A day following IV phenytoin administration, a nurse noticed an IV fluid infiltration on the skin tissue around the left cephalic vein. The area appeared dark blue and purple in color, swollen, erythematous, and warm to touch. An ultrasound of the left upper extremity was performed and revealed subcutaneous fluid collection without evidence of thrombosis. The Naranjo Adverse Drug Reaction Probability Scale assigned a score of 7, indicating phenytoin as the probable cause of purple glove syndrome (PGS). The patient's PGS was managed with a combination of dry dressing material, left forearm elevation, collagenase topical cream, 0.1% IV bupivacaine, and IV fentanyl. The patient's injury was resolving at the time of discharge to a rehabilitation facility. PGS is a rare complication of IV phenytoin therapy. The risk of PGS for this patient may have been abated by decreasing the phenytoin infusion rate from 50 mg/min to less than 25 mg/min.

Population pharmacokinetics of phenytoin in critically ill children

The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration.

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...

An Automated Real-Time Free Phenytoin Assay to Replace the Obsolete Abbott TDx Method

Phenytoin is a commonly used anticonvulsant that is highly protein bound with a narrow therapeutic range. The unbound fraction, free phenytoin (FP), is responsible for pharmacologic effects; therefore, it is essential to measure both FP and total serum phenytoin levels. Historically, the Abbott TDx method has been widely used for the measurement of FP and was the method used in our laboratory. However, the FP TDx assay was recently discontinued by the manufacturer, so we had to develop an alternative methodology. We evaluated the Beckman-Coulter DxC800 based FP method for linearity, analytical sensitivity, and precision. The analytical measurement range of the method was 0.41 to 5.30 microg/mL. Within-run and between-run precision studies yielded CVs of 3.8% and 5.5%, respectively. The method compared favorably with the TDx method, yielding the following regression equation: DxC800 = 0.9**TDx + 0.10; r2 = 0.97 (n = 97). The new FP assay appears to be an acceptable alternative to the TDx method.

Verapamil effect on phenytoin pharmacokinetics in rats

Efflux transporter and enzyme overexpression can be induced by certain antiepileptic drugs. Phenytoin (PHT) is at the same time substrate and inducer of CYP2C isoenzymes and efflux carriers. Its inductive effect has been postulated to be concentration and time-dependent. Since verapamil (VPM) is a well known substrate and inhibitor of P-glycoprotein, its administration could modify PHT systemic exposure. The objective of this work was to determine if single doses (40mg/kg) of VPM might change PHT body fate in the same way when given at the beginning or several days after 100mg/kg of PHT daily doses were started. Both drugs were administered intraperitoneally to female Sprague Dawley rats. VPM increased plasma PHT concentrations after one day of treatment, while a decrease in PHT plasma exposure was observed when VPM was added at the fifth day of the antiepileptic treatment. These results suggested that VPM would have different impact on PHT pharmacokinetics, depending on the level of expression of both efflux transporters and enzymes. Before the hepatic cells could acquire a high content of enzymes due to the inductive effect of PHT dosing, VPM decreased the predominant intestinal clearance of PHT. But, once the enzymatic machinery at the hepatocyte became more important than that at the intestine, although ineffective because of the high hepatobiliary efflux transporter overexpression, VPM blockade from the liver resulted in an increased total PHT clearance.

Phenytoin Removal by Continuous Venovenous Hemofiltration

To describe 2 cases of clinically significant phenytoin removal during continuous venovenous hemofiltration (CVVH) and review the relevant literature regarding phenytoin removal by renal replacement modalities. A 64-year-old female with chronic kidney disease and cirrhosis was admitted to the intensive care unit (ICU) with a traumatic subdural hematoma and seizures. The patient received a loading dose of intravenous phenytoin 1000 mg, followed by maintenance intravenous administration of phenytoin 100 mg and levetiracetam 250 mg every 12 hours. CVVH was initiated for acidosis. A 63-year-old male was admitted to the ICU after cardiac surgery complicated by hypotension. CVVH was initiated for fluid overload, and phenytoin was initiated 3 days later for seizures. A loading dose of intravenous phenytoin 2700 mg was administered, followed by maintenance dosing of intravenous phenytoin 150 mg every 8 hours. Concentrations of unbound phenytoin in serum and CVVH effluent samples were measured during concomitant treatment in each patient. In both patients, serum and effluent concentrations of unbound phenytoin fell steadily while they were on CVVH. Clearance of phenytoin by CVVH was calculated, as was the daily removal of phenytoin, as a percentage of total daily phenytoin dosage during each sampling period. Phenytoin clearance by CVVH ranged from 11 to 13 mL/min in these patients. The clearance of phenytoin with CVVH in these 2 patients was much higher than the renal clearance of phenytoin reported in healthy volunteers with normal renal function. Previous case reports have demonstrated that only small, clinically insignificant amounts of phenytoin are removed by hemodialysis, and the only published report of phenytoin removal by continuous renal replacement therapy used hemofiltration rates much lower than those used in the 2 cases described here. These cases demonstrate that a substantial amount-approximately 30%-of total daily phenytoin dose may be removed by CVVH, and patients may require higher than expected empiric doses. Phenytoin concentrations should be closely monitored in critically ill patients receiving CVVH.

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.

Bioavailability of intravenous fosphenytoin sodium in healthy Japanese volunteers.

To compare and evaluate the bioavailability for intravenous fosphenytoin sodium with that of intravenous phenytoin sodium in Japanese subjects. In study 1, healthy Japanese male volunteers received a 30-min infusion of 375 mg fosphenytoin sodium or an equimolar dose of 250 mg phenytoin by a double-blind, crossover method. In study 2, other healthy Japanese male volunteers received a 30-min or 10-min infusion of 563 mg fosphenytoin sodium, followed by a dose of 750 mg after 2 weeks in an unblinded manner. Comparing with 250 mg phenytoin sodium, 375 mg fosphenytoin sodium exhibited lower total plasma phenytoin C max, whereas the geometric mean ratio of the AUC of total and free phenyotoin for fosphenytoin sodium at a dose of 375 mg was very similar to phenytoin sodium at a equimolar dose of 250 mg (AUC0–t ratio: 0.98 and 1.02, respectively). Therefore, fosphenytoin is almost completely converted to phenytoin in subjects. Fosphenytoin sodium was rapidly converted to phenytoin at doses of 375, 563, and 750 mg. The maximum concentration (C max) of total plasma phenytoin increased in a dose-dependent manner. The area under the plasma concentration–time curve (AUC) increased slightly more than proportionally with the administered dose, and clearance (CL) decreased with increasing dose. Pain and other infusion-site reactions were reported by all 12 subjects with phenytoin sodium, whereas very few symptoms were observed with fosphenytoin sodium. In conclusion, fosphenytoin sodium is considered to be a useful substitute for phenytoin sodium with almost no associated injection-site reactions.

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.

Variability of carbamazepine and valproate concentrations in elderly nursing home residents

Measuring antiepileptic drug (AED) concentrations is common practice in nursing homes. Phenytoin (PHT) concentrations fluctuate substantially in many nursing home residents under constant dose conditions; however, the stability of other AED concentrations has not been studied. We investigated the variability of carbamazepine (CBZ) and valproate (VPA) concentrations under constant dose conditions in US nursing home residents. A database of elderly persons (≥65 years) in 119 nursing homes throughout the US was reviewed for residents with at least one measurement of total PHT, CBZ or VPA. Inclusion criteria for this study were three or more serum concentration measurements while on the same dose of CBZ or VPA, a two-month minimum stay, and no interfering co-medications (inducers or inhibitors). Enrollment occurred over a 2-year period. Data were collected on residents for a minimum of 6 months. Of the 593 residents identified, 245 had CBZ or VPA concentrations measured and 44 (18%) met inclusion criteria (22 on CBZ and 22 VPA). Some subjects had little variability in AED concentrations, others had large fluctuations. Total CBZ concentrations within individuals varied as little as 0mg/L to as much as 6.3mg/L and total VPA concentrations as little as 10.0mg/L to as much as 77.6mg/L. The variability of PHT, CBZ, and VPA concentrations in many but not all nursing home residents implies that a re-evaluation of the role of AED concentration measurements in the management of patients is needed. Strategies for use and interpretation of AED concentration measurements need to be reevaluated.

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.

Total, unbound plasma and salivary phenytoin levels in critically ill patients

OBJECTIVE: To assess the reliability of salivary phenytoin (PHT) concentrations and predicted free PHT levels by Sheiner-Tozer equation in order to substitute measured free PHT concentrations in critically ill patients. METHODOLOGY: Twenty-four neurocritically ill adult patients receiving intravenous PHT were included in the study. Analyses of total, free plasma and saliva PHT concentrations were performed by fluorescence polarization immunoassay. Plasma albumin levels were also determined. RESULTS: Free PHT concentrations as well as salivary levels better correlate to clinical effect than total drug concentrations. Linear regression analysis showed a strong correlation between estimated free PHT concentrations by Sheiner-Tozer and measured free PHT levels (r=0.835; p&lt;0.001) and salivary PHT concentrations and measured free PHT concentrations (r=0.964; p&lt;0.001). Sheiner-Tozer equation could be misleading in the presence of displacing drugs. CONCLUSIONS: Saliva may serve as a feasible fluid to plasma in order to be used as a surrogate for free concentration monitoring of PHT in this population.