Serum Phenytoin Concentrations Research Articles

Can Therapeutic-Range Chronic Phenytoin Administration Cause Cerebellar Ataxia?

Phenytoin (PHT) is a first line antiepileptic drug (AED) used to treat many epilepsy syndromes. As with other AEDs, there are various adverse effects associated with PHT. For this brief review, we searched for evidence of cerebellar ataxia as a chronic adverse effect of therapeutic-range PHT treatment. Many previous studies appeared related to this issue, but many of those studies were designed to resolve questions related to the persistent residual effects of toxic-range PHT therapy, or they were inconclusive due to an absence of critical information such as PHT serum concentration, cerebellar symptoms/signs, and other factors contributing to cerebellar degeneration. Nevertheless, there were a few reports suggesting that cerebellar ataxia may be a chronic adverse effect of therapeutic-range PHT therapy and that a possible pathomechanism for that effect is folate deficiency. Moreover, there is the possibility that there may be patient-specific susceptibility factors affecting ataxia. Further studies are needed to elucidate the incidence, risk factors, and pathomechanism of cerebellar ataxia as a chronic adverse effect of therapeutic-range PHT treatment.

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.

Correlation Between Elimination Parameters of Phenytoin and Carbamazepine in Patients with Epilepsy Receiving Both Drugs Concomitantly: A Preliminary Study

An individualized dosage regimen is of importance for phenytoin and carbamazepine therapy. However, not all patients can afford the cost of therapeutic drug monitoring, particularly in rural areas. An approach used to assist individualized drug therapy is needed. The aim of the study was to determine the relationship between maximum rate of metabolism of phenytoin and carbamazepine clearance. Such information will be beneficial in aiding individualized drug therapy. Thirteen epileptic patients receiving phenytoin in combination with carbamazepine were included in the study. All patients were studied at steady-state conditions with no change in phenytoin and carbamazepine dosage for at least one month before the study commencement. Serum phenytoin and carbamazepine concentrations were determined by Fluorescence Polarization Technique (TDx® Analyzer System). The maximum rate of metabolism of phenytoin (V max) and carbamazepine clearance (CLCBZ ) was calculated based on measured drug levels at steady-state. Subsequently, their relationships were determined by simple linear regression. There was a high correlation coefficient between maximum rate of metabolism of phenytoin (V max) and carbamazepine clearance (CLCBZ) [r = 0.816; p = 0.001 and r = 0.818; p = 0.001 for V max (mg/day) vs. CLCBZ (L/day) and V max (mg/kg/day) vs. CLCBZ (L/kg/day), respectively]. This high positive correlation can be of use in predicting V max from CLCBZ and vice versa, particularly in rural hospitals in Thailand where therapeutic drug monitoring for either one of the drugs is not available. Elimination parameters of phenytoin and carbamazepine can be predicted by their respective relationships. The proposed equations used to determine maximum rate of metabolism of phenytoin and carbamazepine clearance are of benefit in reducing the cost for drug concentration measurements.

Pharmacokinetic Behavior of Phenytoin in Head Trauma and Cerebrovascular Accident Patients in an Iranian Population.

Objective:Acute brain injury is one of the leading causes of morbidity and mortality worldwide. Phenytoin has been commonly used as an anticonvulsant agent for the treatment or prophylaxis of seizures following acute brain injury. After a severe head injury, several pharmacokinetic changes occur. The aim of this study is the comparative evaluation of phenytoin serum concentration in patients with traumatic and nontraumatic brain injury (TBI).Methods:This prospective observational study was performed on twenty adult brain injury patients who were admitted to an Intensive Care Unit and required phenytoin for the treatment or prophylaxis of postinjury seizures. For all the patients, phenytoin serum concentration was determined in three scheduled time points. Phenytoin serum concentration and pharmacokinetic parameters were compared between patients with TBI and cerebrovascular accident (CVA).Findings:The Vmaxand Kmwere significantly higher in head trauma (HT) patients than the CVA group. The phenytoin concentration (Cp) and the Cp/dose ratio were significantly higher in the CVA group patients during the first sampling (P < 0.05). The Acute Physiology and Chronic Health Evaluation П (APACHE П) score was significantly lower than the baseline at the end of the study in each group of patients (P < 0.05). In addition, no significant correlation was observed between Vmax, Km, Cp, Cp/dose ratio, and APACHE II scores at the time of sampling.Conclusion:Due to significant differences in phenytoin plasma concentration and pharmacokinetic parameters between HT and CVA patients, close attention must be paid to the pharmacokinetic behavior of phenytoin in the efforts to improve the patient's outcome after a severe HT.

Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

Association between ABCB1 genetic polymorphism and the effect on epilepsy following phenytoin treatment.

The aim of the study was to analyze the effect of ABCB1 genetic polymorphisms on the efficacy of phenytoin (PHT) treatment in epilepsy patients. In total, 200 epilepsy patients who were administered PHT were divided into the responsive and pharmaco-resistance groups depending on the clinical data of PHT treatment in epilepsy patients. The serum concentration of PHT was detected by high-performance liquid chromatography (HPLC). ABCB1 polymorphisms were analyzed by the polymerase chain reaction restriction-fragment length polymorphism method. The C1236T, C3435T and G2677T/A haplotypes were reconstructed for the ABCB1 gene using SHEsis programs. One-way analysis of variance was used for data analysis. In ABCB1 C1236T, the rate of the CC genotype in pharmaco-resistance (17.5%) was higher than that of the responsive group (2.1%), while the rate of the TT genotype in pharmaco-resistance (41.6%) was lower than that of the responsive group (55.4%) (P<0.05). In ABCB1 G2677T/A, the rate of the GG genotype in pharmaco-resistance (29.6%) was higher than that of the responsive group (9.7%), while the rate of the TT genotype in pharmaco-resistance (4.6%) was lower than that of the responsive group (30.4%) (P<0.05). The rate of the TTC haploid in pharmaco-resistance (24.1%) was higher than that of the responsive group (8.8%) (P<0.05). The PHT serum concentration had no statistical significance in the patients with different genotypes. In conclusion, there was no association between ABCB1 genetic polymorphism and PHT serum concentration, although the polymorphisms affected the efficacy of PHT treatment in patients with epilepsy.

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.

Impact of Body Habitus on Phenytoin Levels Following Fosphenytoin Loading Dose in Pediatric Patients.

Obesity has been shown to affect the disposition of water-soluble medications in pediatric patients. There are no published data describing serum phenytoin concentrations in obese pediatric patients. A retrospective descriptive study was designed that included patients from 2011 to 2013 between 2 and 19 years of age who received a dose of fosphenytoin with a subsequent serum phenytoin concentration, drawn 2-4 hours postloading dose. Body mass index (BMI) was calculated and patients were categorized by BMI percentiles into underweight (<5th percentile), normal weight (5th-84th percentile), overweight (85th-94th percentile), and obese (≥95th percentile). Descriptive statistical analysis and comparisons between groups occurred to determine differences in serum phenytoin concentrations. Multivariable linear regression analysis was performed to determine the effect of body habitus on serum phenytoin concentrations. One hundred ten patients met study criteria (male 51.8%, mean age: 8.3 ± 4.9 years). Patients were normal weight (47.3%), underweight (20.9%), overweight (14.6%), and obese (17.3%). No significant differences were identified between groups in regard to patient demographics, with the exception of weight (P < 0.05). The mean fosphenytoin dose was 23.4 ± 5.7 mg Phenytoin Equivalents (PE)/kg and the serum phenytoin concentration was 22.4 ± 6.8 mg/L measured at 2.9 ± 0.6 hours after dose, and this did not vary significantly across groups (P > 0.05). Multivariable linear regression identified body habitus as a nonsignificant predictor of serum phenytoin concentrations (P > 0.05). Patients of higher BMI did not require further antiepileptic therapy as compared with patients with lower BMI (P > 0.05). Contrary to the adult population, loading dose adjustments do not seem to be required in pediatric patients. Obesity does not affect serum phenytoin concentrations in pediatric patients after intravenous bolus fosphenytoin administration.

Safety, Tolerability, and Pharmacokinetics of Fosphenytoin Loading in Patients With Subarachnoid Hemorrhage.

Fosphenytoin is frequently used for the rapid delivery of phenytoin in subarachnoid hemorrhage (SAH) patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of rapid intravenous loading of fosphenytoin in SAH patients. Fosphenytoin was administered intravenously as a single loading dose of 20 mg phenytoin-equivalent/kg at an infusion rate of 150 mg PE/min to 30 adult patients with SAH, who experienced seizures or had a clinical suspicion of nonconvulsive seizures. Serum concentrations of free phenytoin were determined, and adverse events were assessed at 0, 10, 20 minutes, and 24 hours after the infusion of fosphenytoin. Four patients experienced transient lowering of blood pressure, but other adverse events were not observed. All patients achieved the therapeutic level of free phenytoin (1-2 mg/L) at the end of infusion, but most patients (28/30) entered the markedly supratherapeutic range and the mean serum concentration was 17.7 ± 8.13 mg/L; higher serum concentration was maintained up to 20 minutes after infusion (mean concentration; 3.46 ± 3.75 mg/L). At 24 hours after loading, a majority of the patients (25/30) maintained their levels within the therapeutic range of free phenytoin. Rapid intravenous loading of fosphenytoin was well tolerated and effective in promptly achieving the therapeutic level of free phenytoin, but most patients experienced overshoot of free phenytoin at the end of infusion. Because increased serum concentrations may increase the risk of cardiovascular complications, additional studies are needed to determine the optimal dose and infusion rate of fosphenytoin in SAH patients.

Switching between phenytoin generics in patients with epilepsy may lead to increased risk of breakthrough seizure: chart analysis and practice recommendations.

The Food and Drug Administration (FDA) only requires bioequivalence testing of generic substitutions in order for them to be deemed equivalen to the original product. There may be a large difference of bioavailability among the generic drugs that especially have a narrow therapeutic index, and this may affect clinical outcomes. We aimed to determine whether switching from generic-to-generic equivalent anti-epileptic drugs (AEDs) in patients with epilepsy is associated with clinical outcomes. We performed a retrospective study using the electronic medical records of a tertiary hospital. Adults with a history of epilepsy who used a generic phenytoin and whose therapy was switched to another generic phenytoin between January 2012 and June 2013 were included (n = 80). We compared the drug concentration of phenytoin and seizure events before and after the switch. After switching their generic phenytoin, 33 out of 80 patients (41%) suffered from increasing seizure events (pre-interchange period, 0.44 ± 0.97; post-interchange period, 1.24 ± 2.05; p < 0.0001). The number of medical visits for acute seizure significantly increased in the post-interchange period. The phenytoin serum concentration of all the patients was lesser in the post-interchange period than in the pre-interchange period. (pre-interchange period, 12.79 μg/mL; post-interchange period, 6.36 μg/mL; p < 0.0001). Among the patients with drug resistant epilepsy (DRE), 17 patients (84.2%) had increasing seizure events in the post-interchange period. We confirmed that there was a significant difference in bioavailability between generic phenytoin. Therefore, when using or switching generic anti-epileptic drugs, therapeutic drug monitoring must be done, and the patients' condition must be considered.

Impact of a phenytoin loading dose program in the emergency department.

The use of a combined physician-and pharmacist-directed phenytoin loading dose program in an emergency department (ED) was evaluated. This single-center, observational, preimplementation-postimplementation study evaluated adult patients who received a phenytoin loading dose in the ED. The primary outcome compared the proportion of optimal phenytoin loading doses in the preimplementation and postimplementation groups. The postimplementation group was further stratified into pharmacist- and prescriber-dosing groups. Other outcomes evaluated included the numbers of appropriate serum phenytoin concentrations measured, adverse drug reactions (ADRs), and recurrence of seizures within 24 hours of loading dose administration in the preimplementation and postimplementation groups. There was no difference in the proportion of optimal phenytoin loading doses between the preimplementation and postimplementation groups (50% versus 62%, respectively; p=0.19). When stratified by individual groups, the rate of optimal phenytoin loading doses increased by 64% in the postimplementation pharmacist group (50% versus 82%, p=0.007), while the rate in the prescriber-dosing group remained relatively unchanged (50% versus 49%, p=0.91). The number of appropriate serum phenytoin concentrations significantly improved in the postimplementation versus preimplementation group (65% versus 40%, p=0.025). Rates of ADRs and recurrence of seizures did not differ across the study groups. No change in the percentage of optimal phenytoin loading doses in the ED was observed after implementation of a combined pharmacist- and physician- dosing program. When stratified into pharmacist or prescriber dosing, the pharmacist-led dosing program significantly improved the proportion of patients who received optimal phenytoin loading doses.

The effect of polymorphic metabolism enzymes on serum phenytoin level.

Phenytoin has a widespread use in epilepsy treatment and is mainly metabolized by hepatic cytochrome P450 enzymes (CYP). We have investigated CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants in a Turkish population of patients on phenytoin therapy. Patients on phenytoin therapy (n = 102) for the prevention of epileptic seizures were included. Polymorphic alleles were analyzed by restriction fragment length polymorphism method. Serum concentrations of phenytoin were measured by fluorescence polarization immune assay method. The most frequent genotype was detected for CYP2C9 wild-type alleles (78.43 %), whereas CYP2C19*2/*2 (5.88 %) was the least frequent genotype group. According to the classification made with both enzyme polymorphisms, CYP2C9*1/*1-CYP2C19*1/*1 (G1: 41.17 %) genotype group was the most frequent whereas CYP2C9*1/*2-CYP2C19*1/*3 (G7: 0.98 %) was the least frequent one. The highest mean phenytoin level (27.95 ± 1.85 µg/ml) was detected in the G8 genotype group (CYP2C9*1/*3-CYP2C19*2/*3) and the G1 genotype group showed the lowest mean phenytoin level (7.43 ± 0.73 µg/ml). The mean serum concentration of phenytoin of the polymorphic patients with epilepsy was higher than that for the wild-type alleles both in the monotherapy and polytherapy patients. These results show the importance of the genetic polymorphism analysis of the main metabolizing enzyme groups of phenytoin for the dose adjustment.

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 dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading

IntroductionPhenytoin has complex pharmacokinetics. The intravenous loading dose of phenytoin for children in status epilepticus has recently been increased from 18 to 20 mg/kg. There are no data on the...

Drug Interaction Between Phenytoin and Valproic Acid in a Child With Refractory Epilepsy

Introduction: There are no published reports on pediatric phenytoin toxicity, resulting from the drug interaction between phenytoin and valproic acid. Case description: A 12-year-old patient with refractory epilepsy syndrome presented with phenytoin toxicity, following a concomitant treatment with phenytoin, valproic acid, and lamotrigine. The phenytoin concentration detected in the capsules used by the patient was in accordance with the prescribed dose and was appropriate for the age and weight of the patient. However, a supratherapeutic phenytoin serum concentration was observed (21.92 µg phenytoin/mL of blood). Consequently, the phenytoin dose was reduced, and the patient was monitored; 24 hours later the patient did not present with any signs/symptoms of toxicity. Discussion: Despite the appropriate phenytoin concentration in the capsules, the patient presented with phenytoin toxicity. This toxicity likely resulted from the drug interaction between phenytoin and valproic acid that leads to phenytoin displacement from plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum.

Phenytoin serum concentrations and factors affected after traumatic brain injury

Phenytoin serum concentrations and factors affected after traumatic brain injury

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.

The Quantitative Effect of Serum Albumin, Serum Urea, and Valproic Acid on Unbound Phenytoin Concentrations in Children

Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity.

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.