Therapeutic Drug Monitoring Of Phenytoin Research Articles

The Phenytoin Ataxia Enigma Unveiled ''A Case Report''.

Background: Phenytoin (PHT) has been approved for the treatment of epilepsy. It belongs to the category of medications with a limited therapeutic window and requires therapeutic drug monitoring (TDM). PTH has been observed to induce a variety of Adverse drug reactions (ADRs) including ataxia, dystonia, nystagmus, dyskinesia, etc. Phenytoin-induced ataxia is an uncommonly observed ADR of Phenytoin whose reports are extremely limited. Case: Herein, we present a case report of a 16-year-old Asian patient with a past history of epilepsy that was admitted to a tertiary care hospital due to the development of ataxia, giddiness, and vomiting when taking Phenytoin in addition to Oxcarbazepine, Clobazam, and Levetiracetam to treat seizures. On admission, Magnetic resonance imaging (MRI) findings revealed bilateral variable cerebrospinal fluid (CSF) lesions in the parieto-occipital region of the periventricular area (periventricular leukomalacia). Additionally, serum Phenytoin levels were observed to be in the toxic range (40μg/mL) due to which physicians confirmed the ADR to be due to Phenytoin toxicity. Thus, the Phenytoin drug was discontinued in the patient gradually and he was continued on clobazam, oxcarbazepine, and brivaracetam which led to reversal of the ADR in the patient. Conclusion: In this case, ataxia resulted from Phenytoin overdose, as confirmed by MRI and serum tests suggesting that TDM of Phenytoin is essential to prevent ADRs. Given the scarcity of ataxia cases caused by Phenytoin, awareness is lacking within the scientific community. Our aim is to provide insights to promote better monitoring and patient-centered treatment outcomes for epileptic patients.

Development of a useful single-reference HPLC method for therapeutic drug monitoring of phenytoin and carbamazepine in human plasma.

A single reference high-performance liquid chromatographic (SR-HPLC) method was developed and validated for the therapeutic drug monitoring (TDM) of phenytoin (PHT) and carbamazepine (CBZ) in plasma from patients. The analytical parameters evaluated were linearity, limit of quantification (LOQ), selectivity, accuracy, and stability according to the US Food and Drug Administration (FDA) guideline. The developed method shows good linearity (r2 > 0.999; LOQ-50µg/mL), and LOQ values were 1.56µg/mL for PHT and 0.40µg/mL for CBZ at 254nm. For the development of SR-HPLC method, we evaluated to improve the detection wavelength, stirred retention time, and stability for SR, and selected 5-(p-methylphenyl)-5-phenylhydantoin for PHT (relative molar sensitivity, RMS = 0.848) and 10-methoxyiminostilbene for CBZ (RMS = 0.263). The established differential definite quantities of PHT and CBZ in plasma samples were similar using the RMS and absolute calibration methods based on RSD < 5.10%. A preliminary application was performed using chemiluminescent immunoassay and SR-HPLC method, in which the detectable values of the correlation coefficient and the slope of the intercept were PHT: 0.964 and 0.992647, and CBZ: 0.969 and 1.072089, respectively. Based on these results, we propose that the SR-HPLC method with RMS would be offered to the useful and accurate TDM of various medicines in plasma/serum samples.

Therapeutic drug monitoring of phenytoin and valproic acid in critically ill patients at Windhoek Central Hospital, Namibia.

BackgroundPhenytoin and valproic acid, anticonvulsants, have a low therapeutic index and are highly plasma protein bound, mainly to albumin. Hypoalbuminaemia is common in critically ill patients and increases the unbound drug concentration. Thus, monitoring unbound rather than total plasma drug concentrations is recommended to optimise the dosing of these drugs.ObjectiveThis retrospective study determined unbound plasma concentrations of phenytoin and valproic as a more accurate value of drug levels than total plasma drug concentrations.MethodsTotal plasma concentrations were retrieved for 56 Intensive Care Unit patients for phenytoin and 93 for valproic acid. Total drug concentrations were converted to unbound concentrations using a serum albumin-based normalising equation.ResultsTotal phenytoin plasma concentration was below (41.1% of patients), within (46.4%) or above (12.5%) the therapeutic range (10 μg/mL – 20 μg/mL). However, the predicted unbound plasma concentration of phenytoin was above the therapeutic range (1 μg/mL – 2 μg/mL) in the majority of patients (57.1%). For valproic acid, the total plasma concentration of most patients (87.1%) was below the therapeutic range (50 μg/mL – 100 μg/mL); among remaining patients (12.9%), it was within the therapeutic range. In the majority of patients (91.4%), the predicted unbound plasma concentration of valproic acid was between 2.5 μg/mL and 20 μg/mL.ConclusionThe usefulness of monitoring the total phenytoin or valproic acid levels for dose optimisation is limited as it is an inaccurate indicator of a patient’s drug therapeutic state. Thus, the unbound plasma drug concentrations should be quantified experimentally or predicted in resource-limited settings.

A Novel Correction Equation Avoids High-Magnitude Errors in Interpreting Therapeutic Drug Monitoring of Phenytoin Among Critically Ill Patients.

Phenytoin has a narrow therapeutic index and the potential of under-treatment or toxicity. Available equations are used to correct for the impact of hypoalbuminemia on unbound (free) phenytoin levels. The authors aimed to determine the accuracy of equations used to estimate free phenytoin in hospitalized patients and assess the impact of using additional clinical data. Concurrently measured total and free phenytoin levels in hospitalized patients (2014-2018) were retrospectively evaluated, excluding those from patients on renal replacement therapy and valproic acid. Differences between actual and estimated free phenytoin levels by the original (Original WTZ), Anderson-modified, and Kane-modified Winter-Tozer equations were assessed using Pearson correlations and Bland-Altman analysis. Thereafter, a population-derived formula was developed and validated in a testing cohort. In the 4-year training cohort (n = 81), the Original WTZ equation had the smallest mean difference of all equations. A higher mean difference [-0.362 mcg/mL (95% CI -0.585 to -0.138) vs. -0.054 mcg/mL (95% CI -0.186 to 0.078)] was observed in intensive care unit (ICU) patients compared with non-ICU patients. A cross-validated multivariable model improved the accuracy of free phenytoin estimation in ICU and non-ICU patients, even in the separate testing cohort (n = 52) with respective mean differences of -0.322 mcg/mL (95% CI -0.545 to -0.098) and -0.025 mcg/mL (95% CI -0.379 to 0.329) and was superior to the Original WTZ [mean difference -0.858 mcg/mL (95% CI -1.069 to -0.647) vs. -0.106 mcg/mL (95% CI -0.362 to 0.151), respectively]. Free phenytoin levels in hospitalized patients cannot be accurately determined using available estimation equations, particularly in critically ill patients. Combining ICU status and other available clinical data can improve therapeutic drug monitoring and prevent high-magnitude errors, particularly when free phenytoin assays are not readily available.

Therapeutic drug monitoring of phenytoin using high performance liquid chromatography in a tertiary care hospital of Kashmir, India

Background: Phenytoin is the most commonly used anti-epileptic drug (AED) in this set up due to cost effectiveness and easy availability. Significant fluctuations in serum phenytoin levels leading to toxicities or treatment failures make it an ideal candidate for therapeutic drug monitoring (TDM).Methods: Patients of age ≥18 years who were put on phenytoin were enrolled in this study. Estimation of serum phenytoin levels was done using HPLC. Data was analysed using SPSS version 20.0. Chi square test, Kruskal Wallis test were used to analyse the data.Results: A total of 105 patients enrolled in the study, twenty patients (19%) had normal or therapeutic serum phenytoin levels. Thirty-nine patients (37.2%) had sub therapeutic serum phenytoin levels, while forty-six patients (43.8%) had toxic serum phenytoin levels.Conclusions: The TDM of phenytoin should adopt a multi-disciplinary approach with active involvement of neuro-physicians, pharmacologists, pharmacists and other technical staff for improving the overall management of epilepsy. TDM data will provide the clinicians with greater insight into the factors determining the patient’s response to drug therapy.

Therapeutic Drug Monitoring of Phenytoin by Simple, Rapid, Accurate, Highly Sensitive and Novel Method and Its Clinical Applications

Phenytoin has very challenging pharmacokinetic properties. To prevent its toxicity and ensure efficacy, continuous therapeutic monitoring is required. It is hard to get a simple, accurate, rapid, easily available, economical and highly sensitive assay in one method for therapeutic monitoring of phenytoin. The present study is directed towards establishing and validating a simpler, rapid, an accurate, highly sensitive, novel and environment friendly liquid chromatography/mass spectrometry (LC/MS) method for offering rapid and reliable TDM results of phenytoin in epileptic patients to physicians and clinicians for making immediate and rational decision. 27 epileptics patients with uncontrolled seizures or suspected of non-compliance or toxicity of phenytoin were selected and advised for TDM of phenytoin by neurologists of Qilu Hospital Jinan, China. The LC/MS assay was used for performing of therapeutic monitoring of phenytoin. The Agilent 1100 LC/MS system was used for TDM. The mixture of Ammonium acetate 5mM: Methanol at (35: 65 v/v) was used for the composition of mobile phase. The Diamonsil C18 (150mm×4.6mm, 5μm) column was used for the extraction of analytes in plasma. The samples were prepared with one step simple protein precipitation method. The technique was validated with the guidelines of International Conference on Harmonisation (ICH). The calibration curve demonstrated decent linearity within (0.2-20 µg/mL) concentration range with linearity equation, y= 0.0667855 x +0.00241785 and correlation coefficient (R2) of 0.99928. The specificity, recovery, linearity, accuracy, precision and stability results were within the accepted limits. The concentration of 0.2 µg/mL was observed as lower limit of quantitation (LLOQ), which is 12.5 times lower than the currently available enzyme-multiplied immunoassay technique (EMIT) for measurement of phenytoin in epilepsy patients. A rapid, simple, economical, precise, highly sensitive and novel LC/MS assay has been established, validated and applied successfully in TDM of 27 epileptics patients. It was alarmingly found that TDM results of all these patients were out of safe range except two patients. However, it needs further evaluation. Besides TDM, the stated method can also be applied in bioequivalence, pharmacokinetics, toxicokinetics and pharmacovigilance studies.

Correlation between serum and salivary phenytoin drug metabolite levels to phenytoin influenced gingival overgrowth in adult male subjects. A prospective cohort study

BackgroundTo correlate serum and salivary phenytoin drug metabolite levels in males to phenytoin influenced gingival overgrowth (PIGO). MethodsThirty male patients who are to start with oral phenytoin therapy were recruited. Plaque index (PI), Gingival index (GI), and Oral hygiene index (OHI) were recorded. Basic periodontal therapy was performed. Patients were followed up at 3, 6, 9 and 12 months intervals. Based on the gingival status they were divided in to two groups; Group1 (responders) and Group 2 (non responders). Serum and Salivary samples were analyzed for the drug metabolite levels spectophotometrically. ResultsThe mean values of phenytoin drug metabolite levels in serum of group 1 and group 2 subjects were 14.5±2.6μg/ml and 14.2±1.7μg/ml respectively, with p value of 0.66. The corresponding mean values of phenytoin drug metabolite levels saliva were 1.42±0.34μg/ml and 1.38±0.37μg/ml with p value of 0.75. Correlation of phenytoin drug metabolite to PI, GI, and OHI in both the groups did not show any statistical significance. (R values ranging from −0.229 to 0.434). Correlation between the serum and salivary drug metabolites in both the responder and non responder group also did not show any statistically significant relationship. ConclusionNo correlation between the drug concentration in either the serum or saliva can be correlated to PIGO. Whole Saliva could be a useful tool in therapeutic drug monitoring of phenytoin. Clinical relevanceScientific rationale: To assess and compare the drug metabolite levels in serum and saliva of a neurologic condition where therapeutic drug concentration is of key importance to minimize the side effects. Principle finding: Saliva could be as useful as serum in deciding the drug concentration of phenytoin. And PIGO is not related drug concentrations. Practical implication: Monitoring the drug dosage is of paramount importance for the success of antiepileptic therapy as well as control of its side effects. This longitudinal study confirms that saliva could be an effective alternative to serum for monitoring drug dosage of phenytoin.

Possible False-Negative Results on Therapeutic Drug Monitoring of Phenytoin Using a Particle Enhanced Turbidimetric Inhibition Immunoassay in a Patient With a High Level of IgM

: In this report, the authors described the unusual case of a patient in whom the plasma phenytoin concentration was unexpectedly not detected on a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) technique, a typical immunoassay for phenytoin. The plasma concentration was measured using PETINIA and high-performance liquid chromatography in a 69-year-old male patient treated with fosphenytoin intravenously at the standard dose for 7 days. Although the plasma concentration of phenytoin was below the limit of detection (<0.5 mcg/mL) on PETINIA after the administration of fosphenytoin, the trough plasma concentration was estimated to be between 5 and 10 mg/L on high-performance liquid chromatography. When the plasma concentrations of IgM and IgG were measured using an enzyme-linked immunosorbent assay, the plasma IgG level was within the reference range, whereas the plasma IgM level was 2-3 times higher than the upper limit of the reference range. We concluded that the PETINIA method yielded a possible false-negative result regarding the phenytoin level in this patient, perhaps because of some hindrance to the measurement process by IgM. This case suggests that false-negative results should be considered when therapeutic drug monitoring reveals abnormally low values using PETINIA and that it is necessary to evaluate the plasma IgM level.

Phenytoin: A Guide to Therapeutic Drug Monitoring

Therapeutic drug monitoring of phenytoin is carried out to ensure effective and safe levels. Some of the factors complicating phenytoin dosing include a narrow therapeutic window, high degree of protein binding, and nonlinear pharmacokinetics. However, serum drug levels should only be taken when there is a clear indication to guide patient management. Scenarios where monitoring levels may be clinically useful include: (1) establishing an individual therapeutic concentration, (2) aiding in diagnosis of clinical toxicity, (3) assessing patient compliance, and (4) guiding dosage adjustments in patients likely to have greater pharmacokinetic variability. This paper aims to provide an overview on of the correct timing and interpretation of phenytoin levels. It will also address phenytoin dosing, other monitoring parameters, and management of phenytoin adverse effects.

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

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

Therapeutic Drug Monitoring of Phenytoin in Critically Ill Patients

Therapeutic drug monitoring of phenytoin is necessary to ensure therapeutic and nontoxic levels. Hypoalbuminemia, renal failure, and interactions with other highly protein-bound drugs (e.g., valproic acid) alter protein binding of phenytoin. When these conditions are present, free serum concentrations, which represent the pharmacologically active entity, cannot be predicted from total serum concentrations. Besides general alterations in drug distribution and elimination, protein binding is often altered in critically ill patients. Case reports describe phenytoin toxicity secondary to inappropriate dosage adjustments based solely on total serum concentrations in patients with hypoalbuminemia. Free drug measurements and theoretical equations to facilitate the interpretation of total phenytoin serum levels have been introduced. However, they are not widely implemented in clinical practice because evidence of improvements in patient outcomes is limited. Knowledge of the pharmacokinetic properties of phenytoin is indispensable for correct interpretation of total serum concentrations when protein binding is altered. Free serum concentrations should be measured, or theoretically calculated if measurements are unavailable, to avoid misinterpretation of total serum levels and consequent inappropriate adjustments in the dosage of phenytoin in critically ill patients.

Therapeutic Drug Monitoring of Antiepileptic Drugs

Commonly used conventional antiepileptic drugs for pharmacotherapy in epilepsy are phenytoin, carbamazepine and valproic acid. These drugs have complex pharmacokinetic properties leading to fluctuation in their plasma level at given same therapeutic dose. The present study was done to monitor their plasma levels. A prospective observational study was conducted at National Public Health Laboratory. After taking detail history, blood samples were taken from epileptic patients of all age groups and both gender who were on usual therapeutic dose of one or two combined antiepileptic drugs. Plasma level of these drugs were analyzed by using Fluorescence Polarization Immuno Assay (FPIA) technique. Out of total 417 testing, 81 were tested for phenytoin , 241 for carbamazepine and 95 for valproic acid. Their levels were further analyzed to find therapeutic, subtherapeutic and toxic levels. Out of total 81 blood samples tested for phenytoin, 38.8% had plasma drug at therapeutic level, 38.8% at subtherapeutic level and 28.4% had toxic level. Carbamazepine was tested in 241 samples and 79.3% cases had at therapeutic drug level, 15.8% had subtherapeutic drug level and 4.9% had toxic level. Out of 95 samples tested for valproic acid, 62% had therapeutic level and 20% had subtherapeutic and 18% had toxic level of drug. Therapeutic drug monitoring of phenytoin showed wide fluctuation in its plasma level. Its toxic and subtherapeutic levels were quite high. It is suggested that the dose of phenytoin should be adjusted after regular plasma level monitoring only. Monitoring of carbamazepine and valproic acid were also helpful when their toxicity and efficacy are doubtful.

RP-HPLC determination of valproate concentration in serum

目的 建立反相高效液相色谱法测定人血清中丙戊酸的药物浓度.方法 以symmetryshield RP18柱(5.0 μm,3.9 mm×150 mm)为色谱柱.流动相为甲醇∶水(80∶20),流速1.0 ml/min.Waters 2487双波长紫外检测器,检测波长248 nm.血清用正己烷提取,经α-溴苯乙酮衍生后浓集进样,以环己烷羧酸为内标物.结果 线性范围为5.0～250.0 μg/ml,r=0.9994;平均回收率为98.23%,高、中、低浓度样品的日间和日内测定相对标准偏差(RSD)均小于3%.绪论本法适用于丙戊酸的血药浓度测定。

Appropriate therapeutic drug monitoring of phenytoin

Appropriate therapeutic drug monitoring of phenytoin