Serum Phenytoin Concentrations Research Articles

Phenytoin concentration in people with epilepsy: a comparative study in serum and saliva

In clinical practice, therapeutic drug monitoring (TDM) makes it possible to measure the concentration of drugs in serum or saliva, the purpose of which is to reduce adverse effects and optimize pharmacological therapy. The objective was to determine the concentrations of Phenytoin in saliva and serum of people with epilepsy. Cross-sectional, descriptive study with dynamic recruitment of 30 people with epilepsy (n = 30; 17 men, 56.7% and 13 women, 43.3%; mean age 33.9 ± 11.83 years). Serum and saliva samples were collected at trough levels from patients, who were under phenytoin treatment for at least three months. Drug levels were assessed by the Cloned Donor Enzyme Immunoassay method. Phenytoin levels were found in saliva between 0.01 to 3.56 mg/L and in serum between 0.09 to 36.60 mg/L. Pearson’s analysis showed an association between the estimated serum and saliva phenytoin concentrations (R2 0.7026; 95% CI 0.685-0.921), with a significant statistical correlation (p < 0.05). The Bland-Altman test broke concordance, the difference between the two saliva/serum methods is within 95% confidence. It is concluded that there is an association and concordance between the concentrations of phenytoin in serum and saliva, therefore, this technique can be useful in the clinical monitoring of phenytoin.

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

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

Chronic use of Phenytoin Induced Ataxia: A Case Series of Six Patients

Published on:June 2022 Journal of Young Pharmacists, 2022; 14(2):249-252 Case Report | doi:10.5530/jyp.2022.14.47 Authors: Niharika Pathakamuri1, Sujit Kumar Sah2,*, Atiqulla Shariff2, Siddartha Ningappa Dhurappanavar2, Jalapa Pradhan2, Anjali Pradhan2, Sai Siddharth Matad2, Sinchana Shivukumar2, Dibaneja Khonglein2, Meghna Gosi2, Veer Sangmesh Patil31Department of Pharmacy Practice, TVM College of Pharmacy, Rajiv Gandhi University of Health Sciences, Ballari, Karnataka, INDIA.2Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, Karnataka, INDIA.3Department of Medicine, VIMS Hospital, Vijayanagar Institute of Medical Sciences, Ballari, Karnataka, INDIA. Abstract: Phenytoin-induced ataxia increased the risk of morbidity by 10% to 50% and could be life-threatening but rarely fatal. We reported six cases of phenytoin-induced ataxia, experienced with cerebellar signs of ataxia. All study patients were found with elevated phenytoin serum concentrations (range: 30-40 mcg/ml). Assessment of SARA (Scale for the Assessment and Rating of Ataxia) scale indicated mild ataxia among all patients. Naranjo’s algorithm shows 50% of patients had definite and another 50% had probable relation between phenytoin exposure and ataxia. Ataxia resulted in the withdrawal of phenytoin among five patients and dose reduction in one patient. All patients were treated with alternative antiseizure medications along with supportive treatment and they were symptomatically better within 1-6 weeks duration of treatment. Hence, this study concluded that phenytoin-induced ataxia is common at a plasma concentration of 30 to 40 mcg/ml. Prescribers and pharmacists need to focus on monitoring phenytoin serum levels and providing appropriate counseling to prevent their toxicity.Key words: Ataxia, Chronic use, Naranjo’s algorithm, Neurotoxicity, Phenytoin, Scale for the assessment and rating of ataxia.

Phenytoin-associated movement disorder: A literature review.

Phenytoin (PHT) was first synthesized as a barbiturate derivative and was approved in 1953 by the Food and Drug Administration. This work aimed to review the pathophysiology, epidemiology, clinical presentation, and treatment of PHT-associated movement disorders (MDs). Studies were searched in relevant databases (ScienceDirect, Google Scholar, Excerpta Medica, Latin American and Caribbean Health Sciences Literature, Medline, and Scientific Electronic Library Online) and were selected by two reviewers irrespective of language between 1963 and 2021. Papers of PHT-induced ataxia alone or tremor were excluded. In total, 127 reports with 219 individuals who developed MDs associated with PHT were encountered. MDs found: 126 dyskinesias, 49 myoclonus, 19 dystonia, 14 parkinsonism, 6 tics, 3 stuttering, and 2 restless legs syndrome. The mean age was 35 years (standard deviation [SD]: 23.5) and the predominant sex was male (53.4%). The mean PHT dose when the MD took place was 370.4 mg (SD: 117.5). A serum PHT concentration was reported in 103 cases, ranging from 4 to 110 μg/mL (median: 27.7 μg/mL). No significant relationship was found between PHT dose and age or PHT level. The mean onset time of PHT-associated MD was 23.4 months (SD: 4.4). The mean recovery time after MD management was 3.7 weeks (SD: 1.1). Regarding management, the most common form was PHT withdrawal in 90.4%. 86.3% of the individuals recovered fully. PHT-induced MD was extensively reported in the literature. Only general terms were used in the majority of the reports. The mechanisms underlying the adverse events caused by PHT probably depend on the presence of predisposing factors.

Doxorubicin alters the disposition of phenytoin by reducing its metabolic elimination and binding affinity to serum albumin in rats.

We investigated the pharmacokinetic interaction of doxorubicin (DOX) with phenytoin (PHT) and the underlying mechanism in rats to clarify why the serum PHT concentration decreases despite the impaired PHT metabolic capacity in patients receiving DOX. Rats were administered 15 mg/kg of DOX or saline alone. The pharmacokinetic disposition of intravenously administered PHT was examined 4 days after DOX exposure. Enzyme kinetics of CYP2C-dependent PHT p-hydroxylation were analysed using hepatic microsomes. The unbound PHT concentration in serum was measured by the ultrafiltration method, and the relationship between the unbound fraction (fu) and serum albumin level was assessed. The total clearance (CLtot) of PHT was significantly increased by DOX, but the activity of PHT p-hydroxylation conversely decreased. The unbound serum PHT concentration and its fu were significantly higher in the DOX group than in the control group, and the CLtot/fu, a measure of intrinsic clearance, significantly decreased. An increase in the fu was observed even when using a serum sample with an albumin concentration equal to that in the control group. DOX treatment increases the unbound serum PHT concentration by depressing the metabolic capacity and alters the total PHT by reducing serum albumin and its affinity to PHT.

Intravenous fosphenytoin therapy for rescue of acute trigeminal neuralgia crisis in patients awaiting neurosurgical procedures: A cross-sectional study

Few treatments exist for acute attacks of trigeminal neuralgia. Therefore, this study aimed to investigate the efficacy and safety of an intravenous fosphenytoin therapy protocol in a trigeminal neuralgia crisis. We conducted a single-center, retrospective, observational study of the records of 20 patients with trigeminal neuralgia who received intravenous fosphenytoin therapy (15 mg/mL in normal saline at 50 mg/min for 15 min, total 750 mg) during hospitalization between September 2015 and August 2020. Serum phenytoin concentration was measured 30 min post-infusion. Pain severity was evaluated using a numerical rating scale and was analyzed for statistical significance. The mean age of the patients was 67.5 years (female, 50.0%). The median numerical rating scale score (interquartile range) of pain severity was 2.35 (0–10), 0.65 (0–5), 0.15 (0–1), 2.00 (0–8), and 4.30 (0–10) at 15, 30, and 60 min, and 12 and 24 h, respectively (p < .001); the numerical rating scale score was 10 before treatment. Reduction in pain 24 h following treatment was significant. The mean phenytoin concentration was 12.8 μg/mL 30 min post-treatment. While mild dizziness occurred in four patients, all could walk independently within 60 min. The mean age and weight of patients with mild dizziness were significantly higher and lower, respectively (p < .001), than those of other patients. These results may provide physicians with new insights into the innovative therapeutic option of intravenous fosphenytoin and contribute to advancements in treating acute trigeminal neuralgia crisis.

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.

Influenza immunization does not predominantly alter levels of phenytoin, and cytochrome P-450 enzymes in epileptic patients receiving phenytoin monotherapy

ObjectiveThe study aims to test the effect of influenza vaccination on phenytoin, CYP2C9, and IFNγ levels in epileptic patients receiving phenytoin monotherapy MethodsThirty-one epileptic patients receiving stable-dose phenytoin monotherapy were enrolled onto the study. Serum concentrations of phenytoin, CYP2C9, and IFNγ were compared before and after influenza immunization. The participants were given 0.5 mL of quadrivalent influenza vaccine types A and B subvirion. Blood samples were drawn at baseline, and days 3, 7, 14 post-immunization. The outcomes were levels of phenytoin, CYP2C9, IFNγ, and the incidence of adverse events. ResultsNo significant changes in serum phenytoin, IFNγ, and CYP2C9 levels between baseline and days 3, 7, and 14 after immunization were found. The mean levels of phenytoin, IFNγ, and CYP2C9, respectively, were 11.94 ± 7.43, 1.14 ± 0.98, and 47.69 ± 37.53 pg/mL (baseline); 12.15 ± 6.57, 2.13 ± 3.41, and 49.44 ± 39.83 pg/mL (day 3); 12.19 ± 7.69, 1.15 ± 0.94, and 49.48 ± 33.83 pg/mL (day 7); 12.79 ± 7.94, 2.15 ± 3.11, and 53.65 ± 40.91 pg/mL (day 14). The incidence of vaccine-related adverse events, which were generally mild and resolved without clinical consequences, was 58.1 %. No seizure or changes in seizure frequency were observed during the study. One patient experienced dizziness and ataxia which were symptoms attributed to phenytoin toxicity (34.57 μg/mL) by day 14. ConclusionsInfluenza vaccine has no significant effect on the serum phenytoin and CYP2C9 levels in epileptic patients receiving chronic phenytoin monotherapy. The administration of influenza vaccine to epileptic patients receiving phenytoin monotherapy appears to be safe. Therefore, it is not necessary to routinely measure the serum phenytoin level after influenza immunization.

Evaluation of Two Fosphenytoin Loading Dose Regimens and Monitoring in Infants and Neonates Less Than Six Months of Age.

The objectives of the study were to compare the free serum concentrations after different fosphenytoin loading dose strategies in patients younger than 6 months old and to investigate the frequency of seizure cessation following a loading dose of fosphenytoin. This retrospective cohort study included neonates and infants admitted to a 150-bed children's hospital between August 1, 2014, and February 1, 2018. Patients were included if they were younger than 6 months old and had a postload free phenytoin serum concentration collected during the specified time frame. Patients were identified through a database query screening for the inclusion criteria. Patients were separated into 2 groups with the 15 mg/kg group as per protocol and the 20 mg/kg group as noted in common practice. Data collection included demographic information, fosphenytoin dose, time of administration of the fosphenytoin loading dose, time of sampling, free phenytoin serum concentration results, concomitant antiepileptic agents, albumin serum concentration, and total bilirubin serum concentration. Forty-one patients were included for analysis, 12 in the 15 mg/kg group and 29 in the 20 mg/kg group. The average free phenytoin concentration after the loading dose was 2.45 ± 0.54 mg/L in the 15 mg/kg group and 2.52 ± 0.66 mg/L in the 20 mg/kg group. Seizure cessation after the fosphenytoin loading dose was achieved in 3 of 12 (25%) patients in the 15 mg/kg group and in 13 of 29 (45%) patients in the 20 mg/kg group (p = 0.305). The study demonstrates that a traditional range of fosphenytoin loading dose (15-20 mg/kg) led to elevated postloading dose free phenytoin serum concentrations in the majority of patients with a seizure cessation rate of approximately 39%. The question remains as to what the optimal dose and target concentration should be in this patient population to achieve the best efficacy without risking associated toxicities.

Pharmacological monitoring of antiepileptic drugs in epilepsy patients on haemodialysis.

To retrospectively evaluate the pharmacological profiles of antiepileptic drugs (AEDs) in epilepsy patients during haemodialysis using therapeutic drug monitoring data. The serum concentration of AEDs was collected before and after haemodialysis, and the clearance rate and concentration-to-dose ratio were calculated as pharmacological parameters. Thirty-six patients were enrolled in the study (25 males, 11 females; age: 65.3 ± 14.8 years). In 24 of the 36 patients, epilepsy was associated with cerebrovascular disorders, and diabetes was the most common reason for haemodialysis in 16 patients. With regards to seizure type, focal aware seizures were less frequent than focal impaired awareness seizures and focal-to-bilateral tonic-clonic seizures. Interictal EEG showed intermittent rhythmic slow waves and intermittent slow waves more often than spikes or sharp waves. Levetiracetam was the most commonly used AED and led to the highest percentage of responders (80%; 16/20 patients). However, the clearance rate of levetiracetam during dialysis was highest among the antiepileptic drugs used, requiring supplementary doses after haemodialysis in all 20 patients. Valproic acid was not effective for focal epilepsy for patients on haemodialysis, and non-responders to phenytoin had low serum concentration of phenytoin both before and after haemodialysis. The pre-haemodialysis concentration of levetiracetam tended to be higher than the reference range, suggesting a potential risk of overdosing before haemodialysis. The pre- and post-haemodialysis concentrations of valproic acid tended to be lower than the reference range, suggesting a potential risk of underdosing. The concentration-to-dose ratios for levetiracetam, valproic acid, phenytoin, and carbamazepine were significantly lower after than before haemodialysis. The majority of patients with epilepsy on haemodialysis had cerebrovascular diseases, and therapeutic drug monitoring for levetiracetam, valproic acid, and phenytoin, before and after haemodialysis, is needed to ensure proper dosing.

CYP2C9 polymorphisms are associated with phenytoin toxicity in South-Indian epileptic patients

Background and Aims: The contribution of CYP2C9 in phenytoin metabolism is generally modest, but it increases with increasing serum phenytoin concentration. In the current study, we sought to study the association of CYP2C9*2 and CYP2C9*3 polymorphism with clinical and biochemical phenytoin toxicity in epileptic patients presenting to a tertiary care hospital in South-India. Methods: In total, 50 patients on phenytoin therapy and clinically diagnosed with phenytoin toxicity in neurology outpatient department/casualty/intensive care unit and medicine wards were considered as cases. A total of 50 patients on phenytoin therapy without any evidence of toxicity were considered as controls. CYP2C9*2 (exon-3) and CYP2C9*3 (exon-7) gene polymorphisms were studied using the allele specific PCR method. Results: Out of 100 patients, CYP2C9*2 polymorphism was seen in 8 (8%) patients in which 6 (12%) were cases and 2 (4%) were controls. CYP2C9*3 polymorphism was seen in 23 (23%) patients out of which 17 (34%) were cases and 6 (12%) were controls. Mean serum phenytoin level in cases was 24.23 ± 1.3 μg/ml, whereas in controls, it was 17.10 ± 0.6 μg/ml and the difference was statistically significant with P value Conclusion: Our findings conclude that the presence of CYP2C9*2 and CYP2C9*3 polymorphisms are associated with increased serum phenytoin levels and increased risk of clinical toxicity with phenytoin.

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

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. 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. 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). 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.

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

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. 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. 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. 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.

Effect of age and sex on serum phenytoin concentration in epileptic patients: experience from therapeutic drug monitoring

Background: Phenytoin is a widely prescribed anticonvulsant drug. There is a wide interpatient as well as intrapatient variability in serum phenytoin levels despite standard doses. Phenytoin dosing is challenging because the drug exhibits nonlinear kinetics and interacts with a number of drugs. Children metabolize the drug faster as compared to adults. Ageing is also associated with progressive decline in phenytoin clearance. Many CYP450 enzymes show a sex-dependent difference in activity. The objective for this study was to find the effects of sex and ageing on serum phenytoin levels.Methods: The influence of sex and ageing on the serum phenytoin levels was evaluated retrospectively in 96 anonymized epileptic patients who had received phenytoin alone for more than four weeks. These patients were divided into three age groups, up to 18 years (children), 19-60 years (adults) and more than 60 years (elderly).Results: There were 6.25% children, 84.37% adults and 9.37% elderly. The majority (71.87%) of patients were males. Children achieved a mean phenytoin level of 15.71±4.85 µg/ml after a daily dose of 225.00±75.82 mg. Adults attained a mean serum phenytoin level of 16.12±3.90 µg/ml with a mean daily dose of 282.72±69.44 mg. The elderly achieved a mean serum phenytoin level of 15.85±2.19µg/ml after a mean daily dose of 266.67±70.71 mg. As compared to 77.77% females, 84.05% males had phenytoin levels in therapeutic range. 50.00% children, 82.71% adults, and 100.00% elderly had phenytoin levels in therapeutic range. There was a correlation between sex, age and serum phenytoin levels (r = 0.003 to 0.762).Conclusions: There was a correlation between sex, age and serum phenytoin levels in this study. A better understanding of the effects of sex and age on the clinical pharmacology of phenytoin would enhance the quality of prescribing.

Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex.

Recommended loading doses (LDs) of phenytoin and fosphenytoin range from 10 to 25 mg/kg. Few studies have examined the LD requirements in male versus female patients and in patients who are obese. To examine the influence of obesity and sex on phenytoin LDs. This was a retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following LDs in male versus female and nonobese versus obese patients. An equation used for determining LDs in obese patients was evaluated. There were 141 nonobese and 54 obese patients. When adjusted for total body weight, the obese cohort received a smaller LD than the nonobese cohort (17 mg/kg, interquartile range [IQR] = 14.9-20.0, vs 20 mg/kg, IQR = 18.6-20.0, respectively; P < 0.001). There was no difference between the 2 cohorts in the measured free phenytoin concentration following the LD (obese: 1.7 µg/mL [IQR = 1.4-2.0]; nonobese: 1.8 µg/mL [IQR = 1.5-2.1]; P = 0.16). In the obese cohort, men received a significantly lower weight-based phenytoin dose compared with women (15 mg/kg [IQR = 14.0-19.2], vs 19.9 mg/kg [IQR = 15.0-20.0], respectively; P = 0.008). Postload free phenytoin concentrations were similar between the 2 groups (male: 1.6 µg/mL [IQR = 1.2-2.1]; female: 1.7 µg/mL [IQR = 1.4-2.0]; P = 0.24). Conclusion and Relevance: Phenytoin and fosphenytoin LDs of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations.

A systematic review of phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets in China.

Objective:In this study, we aimed to review the literature on phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets (CPEHTT).Method:A literature search was performed in the following databases: WANFANG DATA, HowNet, National Library Reference and Consultation Alliance, Full-text Database of Foreign Medical Journals, PubMed and Ovid. The search terms were “Compound Phenytoin Sodium, ephedrine Hydrochloride and Theophylline Tablets,” and “poisoning,” or “toxicity,” in Chinese and in English.Result:Ten articles including 104 patients with CPEHTT intoxication were identified. The ages of the patients ranged from 52 to 82 years. Sixty-seven patients were male and thirty-seven patients were female (the male/female ratio, approximately 2:1). The most common clinical manifestations were dizziness (85%) and ataxia (85%), followed by limb weakness (65%), diplopia (25%), binocular horizontal nystagmus (24%), limb numbness (13%), nausea and vomiting (12%), somnolence (10%), tremor and high muscle tension (7%), lag in response (5%), dysarthria (6%), choking cough (2%), auditory hallucination and visual fantasy (1%), and involuntary movement (1%). All patients had chronic lung disease, and the most common disease was chronic bronchitis. The dosage ranged 4 to 15 tablets per day with medication duration of more than 1 year for most patients.Conclusion:The CPEHTT intoxication caused by phenytoin toxicity represents a drug safety problem in China. The common clinical manifestations, serum phenytoin concentrations, and associated factors of CPEHTT intoxication are important for diagnosis and prevention. These findings may help guide clinicians to correctly attend to the use of CPEHTT and avoid its toxicity.

Correlation between measured and calculated free phenytoin serum concentration in neurointensive care patients with hypoalbuminemia.

PurposeIn critically ill patients, monitoring free phenytoin concentration is a valuable method for phenytoin-dosage adjustment. However, due to technical difficulties and the high cost of these methods, the Sheiner–Tozer equation is routinely used for estimating free phenytoin concentration in clinical practice. There have been conflicting results concerning accuracy and precision of the Sheiner–Tozer equation for prediction of free phenytoin concentration in various patient populations. Therefore, this study was conducted to evaluate the accuracy and correlation of measured and calculated free phenytoin concentrations in neurointensive care patients with hypoalbuminemia.MethodsA total of 65 adult neurointensive care patients with hypoalbuminemia who were receiving phenytoin for prevention or treatment of seizures were recruited in this study. In addition to measuring free phenytoin concentration by HPLC, free phenytoin concentration was calculated using both conventional and revised Sheiner–Tozer equations. Eventually, the correlation and level of agreement between measured and calculated free phenytoin concentrations were evaluated.ResultsThe mean albumin concentration of studied patients was 2.63±0.57 g/dL. There was a significant but weak–moderate correlation between measured and calculated free phenytoin concentration using conventional and revised Sheiner–Tozer equations (r=0.45 and r=0.43, respectively). Conventional and revised Sheiner–Tozer equations were not able to predict free phenytoin concentrations accurately in 33.85% and 35.4% of patients, respectively. Although the sex of patients did not have a significant impact on the level of agreement, younger patients had a higher level of agreement.ConclusionAlthough there was a moderate correlation between calculated and measured free phenytoin concentration, the Sheiner–Tozer equation was not able to predict free phenytoin concentration accurately in all patients, especially in older patients. Therefore, monitoring free phenytoin serum concentration besides clinical outcomes should be considered for phenytoin-dose adjustment in critically ill patients.

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

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

Reply: Selection Bias in Study Participants with Acute Hypercapnic Respiratory Failure.

We reexamined the efficacy of the clinically effective anticonvulsant drug phenytoin in the kindling model. We investigated the effects of varying doses of intravenous phenytoin on serum concentrations and on several indexes of stimulation-evoked kindled seizures. Intravenous phenytoin produced a dose-dependent increase in serum phenytoin concentration and powerfully suppressed both limbic and clonic motor seizures. Although focal afterdischarge threshold was elevated to some extent, the most profound effect of phenytoin was limitation of seizure propagation. Variable and low serum concentrations of intraperitoneal or oral phenytoin may explain previous findings that phenytoin is only partly effective or ineffective against kindled seizures. Together with previous results with other drugs, the excellent correlation among drugs effective against human and kindled seizures strengthens the validity of this model. We suggest that the efficacy of experimental anticonvulsant drugs be established in the kindling model before initiation of clinical trials for partial and secondarily generalized seizures.

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.