Utility of monitoring the serum levetiracetam concentration for intraoperative seizure control during awake craniotomy.

Awake craniotomy is an established procedure for resecting brain tumors in eloquent lesions, and intraoperative seizure is one of the most important complications. Phenytoin is normally used to control intraoperative seizures. Recently, phenytoin was replaced with levetiracetam at our institution because the latter has fewer side effects. While the phenytoin dose is calibrated in accordance with the serum concentration, there is currently no consensus on a method of monitoring the serum concentration of levetiracetam or the effective concentration range needed to control intraoperative seizures during awake craniotomy. The present study therefore aimed to determine whether monitoring the serum levetiracetam concentration is useful for controlling intraoperative seizures during awake craniotomy. The intraoperative serum concentration of levetiracetam during awake craniotomy was measured in 34 patients and compared with that of phenytoin in 33 patients undergoing the same procedure. The levetiracetam concentration inversely correlated with body surface area (BSA) and estimated glomerular filtration rate (eGFR). Levetiracetam was superior to phenytoin in terms of the correlation between the serum concentration and the dose adjusted for BSA and eGFR (correlation coefficient, 0.49 vs 0.21). Furthermore, the serum levetiracetam concentration in patients with intraoperative seizures was below the 95% confidence interval (CI) of the regression line whereas the serum phenytoin concentration of two patients with seizures was within the 95% CI, indicating that evaluating the serum levetiracetam concentration against the BSA and eGFR-adjusted dosage may be useful in preventing intraoperative seizures during awake craniotomy by allowing prediction of the seizure risk and enabling more accurate dosage calibration.

A pharmacokinetic simulation study to assess the performance of a sparse blood sampling approach to quantify early drug exposure.

Estimating early exposure of drugs used for the treatment of emergent conditions is challenging because blood sampling to measure concentrations is difficult. The objective of this work was to evaluate predictive performance of two early concentrations and prior pharmacokinetic (PK) information for estimating early exposure. The performance of a modeling approach was compared with a noncompartmental analysis (NCA). A simulation study was performed using literature-based models for phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA). These models were used to simulate rich concentration-time profiles from 0 to 2 h. Profiles without residual unexplained variability (RUV) were used to obtain the true partial area under the curve (pAUC) until 2 h after the start of drug infusion. From the profiles with the RUV, two concentrations per patient were randomly selected. These concentrations were analyzed under a population model to obtain individual population PK (PopPK) pAUCs. The NCA pAUCs were calculated using a linear trapezoidal rule. Percent prediction errors (PPEs) for the PopPK pAUCs and NCA pAUCs were calculated. A PPE within ±20% of the true value was considered a success and the number of successes was obtained for 100 simulated datasets. For PHT, LEV, and VPA, respectively, the median value of the success statistics obtained using the PopPK approach of 81%, 92%, and 88% were significantly higher than the 72%, 80%, and 67% using the NCA approach (p < 0.05; Mann-Whitney U test). This study provides a means by which early exposure can be estimated with good precision from two concentrations and a PopPK approach. It can be applied to other settings in which early exposures are of interest.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. AIM OF THE STUDY: The present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. MATERIALS AND METHODS: Wistar rats (175-200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. RESULTS: The VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. CONCLUSION: The results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.

Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling.

BACKGROUND AND OBJECTIVE: Phenytoin is extensively protein bound with a narrow therapeutic range. The unbound phenytoin is pharmacologically active, but total concentrations are routinely measured in clinical practice. The relationship between free and total phenytoin has been described by various binding models with inconsistent findings. Systematic comparison of these binding models in a single experimental setting is warranted to determine the optimal binding behaviors. METHODS: Non-linear mixed-effects modeling was conducted on retrospectively collected data (n = 37 adults receiving oral or intravenous phenytoin) using a stochastic approximation expectation-maximization algorithm in MonolixSuite-2019R2. The optimal base structural model was initially developed and utilized to compare four binding models: Winter-Tozer, linear binding, non-linear single-binding site, and non-linear multiple-binding site. Each binding model was subjected to error and covariate modeling. The final model was evaluated using relative standard errors (RSEs), goodness-of-fit plots, visual predictive check, and bootstrapping. RESULTS: A one-compartment, first-order absorption, Michaelis-Menten elimination, and linear protein-binding model best described the population pharmacokinetics of free phenytoin at typical clinical concentrations. The non-linear single-binding-site model also adequately described phenytoin binding but generated larger RSEs. The non-linear multiple-binding-site model performed the worst, with no identified covariates. The optimal linear binding model suggested a relatively high binding capacity using a single albumin site. Covariate modeling indicated a positive relationship between albumin concentration and the binding proportionality constant. CONCLUSIONS: The linear binding model best described the population pharmacokinetics of unbound phenytoin in adult subjects and may be used to improve the prediction of free phenytoin concentrations.

Electromembrane extraction as a new approach for determination of free concentration of phenytoin in plasma using capillary electrophoresis.

PURPOSE: Electromembrane extraction is a new membrane-based extraction method in which charged compounds are extracted by an electric field. So far, this method has been used to extract and isolate a variety of acidic and basic drugs from various samples, including blood and plasma. However, in this procedure, it is not yet clear whether only unbound fraction of a drug is extracted or the total drug. The aim of this study is to reveal the nature of drug extraction in the presence of plasma proteins. METHODS: To determine the nature of the extraction, the electromembrane extraction was performed from plasma solutions of phenytoin with concentrations 0.03 and 1.0 µg/mL, then the result was compared with the values obtained from the electromembrane extraction of ultrafiltrate of the same solutions (free concentration) and protein-free ultrafiltrate of plasma with final concentration of 0.03 and 1.0 µg/mL (total concentration). For this purpose, EME followed by capillary electrophoresis coupled with diode array detection was optimized and validated. RESULTS: The results showed that the electromembrane extraction method was only able to extract the unbound fraction of phenytoin from plasma samples. The method was validated over a concentration range of 0.03-4 µg/mL. The inter and intra-assay precisions were less than 6.7%. The phenytoin protein binding was also determined to be in agreement with the literature data and confirms the validity of this method. CONCLUSION: This sensitive and quick EME approach for determining the free concentration of a phenytoin, can be a good alternative to classic methods for therapeutic drug monitoring and pharmacokinetic studies.

Predicted values for human total clearance of a variety of typical compounds with differently humanized-liver mouse plasma data.

Prediction of human pharmacokinetics is important in the preclinical stage. Values for total clearance of compounds from plasma should be one of the most important pharmacokinetic parameters for predictions. Although several physiological and empirical methods including single-species allometry for prediction of values for human clearance of compounds using humanized-liver mice have been reported, further improvement of prediction accuracies would be still expected. To optimize these approaches, we proposed methods for unbound intrinsic clearance in virtually 100% humanized-liver mouse by incorporating unbound plasma fractions of compounds in differently humanized-liver mice. Comparisons of prediction accuracies of values for human clearance of 15 model compounds were performed among our current physiological and previously reported models and single-species allometry using humanized-liver mice. Incorporation of the actual unbound plasma fractions of compounds and correction of residual mice hepatocyte in humanized-liver mice showed comparable prediction accuracy to that by single-species allometry. After exclusion of 3 compounds with large species differences in values of clearance and unbound plasma fractions between mice and humans out of 15 compounds, prediction accuracies were improved in the methods investigated. The previously and present reported physiological methods could show the good prediction accuracy of values for clearance of drugs from plasma.

Analytical validation of a quantitative method for therapeutic drug monitoring on the Alinity®c Abbott.

OBJECTIVE: The aim of this study was to evaluate the analytical performance of the Alinity®c Abbott compared to the Architect® immunoassay system for the determination of drugs having a narrow therapeutic index. METHODS: Valproic acid, amikacin, gentamicin, phenobarbital and vancomycin were analyzed using Particle-Enhanced Turbidimetric Inhibitor Immunoassay (Petinia), phenytoin and theophylline were analyzed using an immunoenzymatic method and a colorimetric method was performed to quantify lithium. The methods were validated according to the total error approach. Seven validation standards were analyzed in quintuplet during four days to establish the limits of the methods. Dilution integrity and interferences (hemolysis and high concentrations of bilirubin and lipids) were also tested. Depending on the analyte, the results obtained for twenty to forty patients on the Alinity® were compared to those obtained on the Architect®. RESULTS: The bias and the coefficients of variation for repeatability and for intermediate precision were lower than 15% for all drugs. Accuracy profiles were acceptable (acceptance limits fixed at 30%) in the validated ranges. The lower limits of quantification (LLOQ) were similar to those determined by Abbott except for gentamicin for which we determined a LLOQ at 1.22 mg/L while Abbott determined it at 0.5 mg/L. All assays diluted linear and analyte concentrations were not affected by interferences. Concentrations obtained for real samples on the Alinity®c are comparable to those obtained on the Architect®ci. CONCLUSIONS: The analytical validation of a method suitable for therapeutic drug monitoring of drugs on the Alinity®c meets the requirements of European Medicines Agency.

Estudio del índice nivel/dosis de la fenitoína en pacientes epilépticos voluntarios de Mérida / Study of the level/dose index of phenytoin in volunteer epileptic patients from Mérida

INTRODUCCIÓN La fenitoína es usada con mucha frecuencia en nuestro medio, por lo que se requiere hacer estudios de monitorización terapéutica, que contribuya a minimizar los efectos adversos y optimizar la terapia farmacológica. En ese contexto, nuestro objetivo ha sido determinar el índice nivel/dosis de la fenitoína en pacientes epilépticos voluntarios de Mérida. MÉTODOS Se realizó un estudio descriptivo, observacional y por reclutamiento consecutivo concurrente, conformado por 30 pacientes voluntarios con diagnóstico de epilepsia. Las muestras de suero se obtuvieron en niveles mínimos de pacientes que estaban en tratamiento con fenitoína durante 1 mes. Los niveles del fármaco se cuantificaron por el método de Inmunoensayo de enzima donante clonada en el equipo Indiko Thermo Scientific. RESULTADOS El índice nivel/dosis fue de 1,4 y 1,6, la concentración plasmática de 4,8mg/l y 8,0mg/l, la capacidad metabólica de 388,4 y 462,9mg/día, respectivamente en mujeres y hombres. Mientras que el nivel de la concentración plasmática en el estado estacionario fue de 6,5mg/l y 5,5mg/l, la dosis de carga máxima de 237,3mg y de 395,6mg, respectivamente en mujeres y hombres con epilepsia de la ciudad de Mérida. CONCLUSIONES Nuestros resultados sugieren que se debe individualizar la dosis en base al índice nivel/dosis de cada paciente, ya que no se puede extrapolar para todos los pacientes con epilepsia, debido a diversos factores como al fenotipo metabólico y al uso de fármacos inductores e inhibidores enzimáticos.

INTRODUCTION Phenytoin is used very frequently in our environment, so it is necessary to do studies of therapeutic monitoring, which helps to minimize adverse drug reaction and optimize pharmacological therapy. In this context, our objective was to determine the level/dose index of phenytoin in volunteer epileptic patients from Mérida. METHODS A descriptive, observational and consecutive concurrent recruitment study was carried out, consisting of 30 volunteer patients with a diagnosis of epilepsy. The serum samples were obtained in minimum levels from patients who were in treatment with phenytoin for 1 month. The levels of the drug were quantified by the method of donor enzyme immunoassay cloned in the Indiko Thermo Scientific equipment. RESULTS The level/dose index was 1,4 and 1,6, the plasma concentration of 4,8mg/l and 8,0mg/l, the metabolic capacity of 388,4 and 462,9mg/day, respectively in women and men. While the level of plasma concentration at steady state was 6,5mg/l and 5,5mg/l, the maximum loading dose of 237,3mg and 395,6mg, respectively in women and men with epilepsy of the city of Mérida. CONCLUSIONS Our results suggest that the dose should be individualized based on the level/dose index of each patient, since it can not be extrapolated for all patients with epilepsy, due to various factors such as the metabolic phenotype and the use of enzyme-inducing drugs and inhibitors.

Efficacy, Tolerability and Serum Phenytoin Levels after Intravenous Fosphenytoin Loading Dose in Children with Status Epilepticus.

OBJECTIVE: To evaluate the efficacy and tolerability of intravenous fosphenytoin in children with status epilepticus, and resulting serum total phenytoin levels. METHODS: In this prospective study, 51 children aged less than 18 years received intravenous loading dose of fosphenytoin (18-20 mg/kg). Serum total phenytoin levels were estimated at 90 -100 minutes. Outcomes studied were (i) seizure control and local and/or systemic adverse effects in next 24 hours and (ii) phenytoin levels and its correlation with dose received, seizure control and adverse effects. RESULTS: The actual dose of fosphenytoin received varied from 15.1 to 25 mg/kg. Seizures were controlled in 45 (88%) children and, two required additional dose of 10 mg/kg. None of the children showed any local or systemic adverse effects. Serum total phenytoin levels were in the therapeutic range (10-20 µg/mL) in 12 (23.5%), sub-therapeutic in 16 (31.3%) and supra-therapeutic in 25 (49%) children. There was weak correlation of the phenytoin levels with dose of fosphenytoin received, seizure control, or adverse effects. CONCLUSIONS: Intravenous fosphenytoin loading dose of 20 mg/kg is effective in controlling seizures in 88% of children with status epilepticus, with a good safety profile. Seizure control and adverse effects appear to be independent of serum total phenytoin levels achieved.

Diagnostic evaluation and management of seizures and status epilepticus in children with known epilepsy or new-onset seizures: A retrospective and comparative analysis.

OBJECTIVES: The purpose of this study was to describe and compare the initial management, including clinical/biological investigation and treatment, of new-onset seizures and status epilepticus (SE) in children versus seizures and SE in those with known epilepsy. METHODS: This was a retrospective, single-center, observational study conducted in an urban pediatric hospital in Paris. All patients, aged from 1 month to 18 years, admitted to the pediatric intensive care unit, the high-dependency care unit, and those who required hospitalization in the short-term unit of the emergency department between January 1 and December 31, 2014 for seizures and/or SE were included. RESULTS: We analyzed the data of 190 children: new-onset seizures (N=118; group A) versus those with known epilepsy (N=72; group B). At least one diagnostic test was performed on 156 patients (82.1%) (group A, N=104, 88.1%; group B, N=52, 72.2%; P=0.05). In group B, blood levels of antiepileptic drugs were measured in 14 of the 38 patients with SE, of whom six were under dosed. Treatments were: first line, diazepam (group A, 80%; group B, 46%; P<0.001); second line, diazepam (group A, 56%; group B, 34%; P=0.02) or clonazepam (group A, 24%; group B, 46%; P=0.001); third line, phenytoin (group A, 54%; group B, 22%; P<0.001) or clonazepam (group A, 18%; group B, 61%; P<0.001). CONCLUSION: Diagnostic evaluation and treatment should be individualized for children with known epilepsy.

Phenytoin intoxication associated with omeprazole administration in a child with defective CYP2C9.

Adverse drug reactions occur at a high rate in hospitalized children, frequently due to antiepileptic drug administration. Phenytoin is a commonly used drug, and its metabolism is mediated by a specific cytochrome-P450 isoform, CYP2C9, which is encoded by a polymorphic gene. It is worth noting that very frequently administered drugs, such as proton pump inhibitors, compete with phenytoin for CYP2C19-mediated metabolism. Here we describe a case of phenytoin intoxication in a child with defective CYP2C9, after omeprazole administration.

Intoxicación por fenitoína. Reacción cruzada con barbitúricos / Phenytoin intoxication. Cross-reaction with barbiturates

Las intoxicaciones suponen un motivo frecuente de consulta en Pediatría. El cribado toxicológico en orina es una herramienta de diagnóstico rápido y bajo coste, pero debemos tener precaución en su interpretación, ya que existen reacciones cruzadas con otros fármacos de estructura química similar. Se describe el caso clínico de un paciente de 11 años con afectación neurológica y resultados positivos para barbitúricos en orina. La confirmación de niveles elevados de fenitoína en sangre permite confirmar el diagnóstico y la reactividad cruzada de los resultados en orina

Intoxications are a common reason for consultation in Pediatrics. Urine toxicology screening is a rapid and low-cost tool, but these results have to be interpreted with caution due to cross reactions with other drugs with similar chemical structure. We describe the clinical case of a 11 years old patient with neurological involvement and positive results for barbiturates in urine. Confirmation of high levels of phenytoin in blood guaranteed the diagnosis and cross-reaction results in urine

Intoxicación por fenitoína. Reacción cruzada con barbitúricos / Phenytoin intoxication. Cross-reaction with barbiturates

Las intoxicaciones suponen un motivo frecuente de consulta en Pediatría. El cribado toxicológico en orina es una herramienta de diagnóstico rápido y bajo coste, pero debemos tener precaución en su interpretación, ya que existen reacciones cruzadas con otros fármacos de estructura química similar. Se describe el caso clínico de un paciente de 11 años con afectación neurológica y resultados positivos para barbitúricos en orina. La confirmación de niveles elevados de fenitoína en sangre permite confirmar el diagnóstico y la reactividad cruzada de los resultados en orina

Intoxications are a common reason for consultation in Pediatrics. Urine toxicology screening is a rapid and low-cost tool, but these results have to be interpreted with caution due to cross reactions with other drugs with similar chemical structure. We describe the clinical case of a 11 years old patient with neurological involvement and positive results for barbiturates in urine. Confirmation of high levels of phenytoin in blood guaranteed the diagnosis and cross-reaction results in urine

The Evolution of Population Pharmacokinetic Model of Oral Phenytoin for Early Seizure Prophylaxis Post-Craniotomy.

BACKGROUND: This study aimed to re-establish a Population Pharmacokinetic (PPK) model of oral phenytoin to further optimize the individualized medication regimen based on our previous research. METHODS: Patients with intracranial malignant tumor requiring craniotomy were prospectively enrolled according to the inclusion criteria. Genotypes of CYP2C9*1 or *3 and CYP2C19*1, *2 or *3 were determined by real time PCR (TaqMan probe) method. Serum concentrations of phenytoin on the 4th and 7th day after oral administration were determined using fluorescence polarization immunoassay. The PPK parameters were estimated using Nonlinear Mixed Effects Models (NONMEM) and internal validation was performed using bootstraps. The predictive performance of the final model was evaluated by Normalized Predictive Distribution Errors (NPDEs) and diagnostic goodness- of-fit plots. RESULTS: A total of 390 serum samples were collected from 170 patients in PPK model building group. The population typical values for Vm, Km and the apparent volume of distribution (V) in the final model were 17.5 mg/h, 6.41 mg/L and 54.8 L, respectively. Internal validation by bootstraps showed that the final model was stable and reliable. NPDEs with a normal distribution and a scatterplot with symmetrical distribution showed that the final model had good predictive capability. Individualized dose regimens of additional 40 patients in the external validation group were designed by the present final PPK model. The percentages of patients with serum concentrations within the therapeutic range were 61.53% (24/39) on the 4th day and 94.87% (37/39) on the 7th day, which were higher than the 39.33% (59/150) and 52.10% (87/167) of above 170 patients (P < 0.0001). CONCLUSION: The present PPK final model for oral phenytoin may be used to further optimize phenytoin individualized dose regimen to prevent early seizure in patients after brain injury if patient characteristics meet those of the population studied.

In-situ microscale spectrophotometric determination of phenytoin by using branched gold nanoparticles.

A rapid method for the sensitive detection of phenytoin (PHT) by branched gold nanoparticles (B-AuNPs) is described. These nanoparticles were synthesized by adding methanol as the reducing agent and poly(ethylene glycol) as the stabilizer at 70 °C. The B-AuNPs are red in color with an absorption maximum at 540 nm when prepared in situ. However, the color becomes increasingly weaker when PHT is present in increasing concentrations. This method can determine PHT over the 67-670 ng·mL-1 concentration range, with detection limit of 21 ng·mL-1. The relative standard deviation for five replicate measurements at 68 and 530 ng·mL-1 of PHT was 3.2% and 1.2%, respectively. The method was applied to the determination of PHT in plasma samples of epileptic patients, and the results were in agreement with those obtained by a standard official method. Graphical abstract Branched gold nanoparticles (AuNPs) prepared in situ have a red color with an absorption maximum at 540 nm. The color becomes increasingly weaker with decreasing the intensity of the characteristic SPR band when PHT is present in increasing concentration. The current assay is capable of determining PHT over the 67-670 ng·mL-1 concentration range with a limit of detection of 21 ng·mL-1.

Population Pharmacokinetic Analysis of Phenytoin After Intravenous Administration of Fosphenytoin in Adult and Elderly Epileptic Patients.

BACKGROUND: Fosphenytoin, the diphosphate ester salt of phenytoin, is widely used to treat status epilepticus. The aim of this study was to develop a population pharmacokinetic (PPK) model to describe serum phenytoin concentrations after the intravenous administration of fosphenytoin in adult and elderly epileptic patients. METHODS: Patient backgrounds, laboratory tests, and prescribed drugs were retrospectively collected from electronic medical records. Patients who received fosphenytoin were enrolled. The PPK analysis was performed using NONMEM 7.3.0 with the first-order conditional estimation method with interaction. Age, sex, laboratory tests, and coadministered drugs were selected as candidates for covariates. Significance levels for forward inclusion and backward elimination were set at 0.05 and 0.01, respectively. The study protocol was approved by the Fukuoka Tokushukai Ethics Committee. RESULTS: A total of 340 serum phenytoin concentrations from 200 patients treated with fosphenytoin were available. The median age and body weight of the population were 71 years and 53.4 kg, respectively. A linear 1-compartment model with the conversion rate of fosphenytoin to phenytoin clearly described the pharmacokinetics of phenytoin after the intravenous administration of fosphenytoin. Age was detected as a covariate of clearance (CL): CL (L/h) = 1.99 × (body weight/53.4) × (age/71). Goodness-of-fit plots revealed the high-predictive performance of the final PPK model, and systematic deviations were not observed. The final model was validated by a prediction-corrected visual predictive check and bootstrap analysis. CONCLUSIONS: We herein developed a PPK model to describe phenytoin concentrations after the intravenous administration of fosphenytoin. Age was identified as a significant covariate for CL.

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

STUDY OBJECTIVE: 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. DESIGN: Retrospective chart review. SETTING: Large academic medical center. PATIENTS: A total of 344 patients with free and total phenytoin, albumin, and serum creatinine concentrations obtained between November 2012 and May 2017. MEASUREMENTS AND MAIN RESULTS: 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 90 ml/min/1.73 m2 , 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%. CONCLUSION: 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.

Phenytoin-induced hypothermia.

A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on admission. Routine work-up revealed toxic levels of phenytoin. No cause of hypothermia could be identified but as his phenytoin levels normalised, his body temperature also improved. There are three other reported cases of phenytoin- induced hypothermia in the literature. Could this be a rare cause of hypothermia?

Dosage of phenytoin in neurocritical patients using Bayesian algorithms: a pilot study.

Phenytoin is widely used in neurocritical patients. Owing to its high pharmacokinetic variability and narrow therapeutic range, plasma level-guided dosing has become the standard. Bayesian prediction (BP) is considered the most flexible and precise pharmacokinetic strategy among several options. A retrospective study of BP dosage adjustment in 20 patients (35 plasma measures) was developed. Results indicated that 70% of phenytoin plasma levels of first plasma samples were beyond the therapeutic range. Phenytoin doses were also estimated according to BP for all patients. The measurements confirmed the ability of the strategy to lead to optimal dosage in 80% of patients, thus indicating a three-fold improvement over the basing dosage adjustment recommended in the literature.

A new method for simultaneous quantification of fosphenytoin, phenytoin and its primary metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin in whole blood by ultra-performance liquid chromatography-tandem mass spectrometry.

A method for simultaneous quantification of fosphenytoin (F-PHT), phenytoin (PHT) and its main metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in whole blood was developed and validated using ultra-performance liquid chromatography-tandem mass spectrometry. Whole blood samples were pretreated by liquid-liquid extraction with acetonitrile and methanol. Chromatographic separation was performed using a CORTECS™ UPLC® C18 (2.1 × 50 mm i.d., particle size 1.6 µm) analytical column, and water containing 10 mM ammonium formate and acetonitrile as the mobile phase. Quantification of the analytes was carried out using mass chromatography with each product ion referenced against phenytoin-d10 as an internal standard. Calibration curves exhibited good linear relationships in a range from 0.005 to 50 µg/ml with correlation coefficients exceeding 0.995. The limits of detection were estimated to be 0.002-0.01 µg/ml. The accuracies and precisions were 96.2-104.3% and 0.7-10.7%, respectively. The recovery efficiencies were in the range of 42.4-59.2%. Matrix effects were observed for PHT and HPPH, with signal suppression ranging from -6.6 to -32.2%. Matrix effect for F-PHT (-5.0 to 8.9%) was less than those for PHT and HPPH. All analytes were stable under different storage conditions. This method was successfully applied for the quantification of F-PHT, PHT and HPPH in rat whole blood samples taken after bolus intravenous administration of F-PHT.