Phenytoin Levels Research Articles

B-287 Comparing a Recently FDA-Cleared Free Phenytoin Assay to a Laboratory Developed Test

Abstract Background Phenytoin is an anti-convulsant drug that is commonly prescribed to epileptic patients to control seizures. The drug circulates in two forms: protein-bound (90%), and the free, biologically active form (10%). In certain circumstances, such as protein-binding disruption, hypoalbuminemia, and drug-drug interactions, the total phenytoin serum concentration may not accurately reflect active phenytoin levels. Therefore, a free phenytoin level (i.e. non-protein bound) may be indicated. Until recent FDA-clearance, we utilized an in-house, laboratory-development test (LDT) to deliver these needed results. The purpose of this study was to validate the FDA-cleared assay and compare its performance characteristics to a free phenytoin LDT. Methods Validation of the FDA-cleared assay was performed on an automated chemistry analyzer (Roche Diagnostics, cobas c502), utilizing a kinetic interaction of microparticles in a solution (KIMS) method. Both the FDA and LDT assay used the same free phenytoin reagent, however the calibrators and pipetting parameters for each assay were different. FDA assay used a six-point calibration at concentrations of: 0, 2.5, 5, 10, 20, 40 µg/mL (Preciset TDM I Calibrators), whereas the LDT assay used a six-point calibration at concentrations of: 0.0, 0.5, 1.0, 2.0, 3.0, 4.0 µg/mL (cobas FP Free Phenytoin Calibrators). The following performance characteristics were determined for the FDA-cleared assay and compared to the current LDT: analytical measurement range, precision, accuracy, and maximum dilution. Free forms of the drug were obtained as a filtrate through centrifugation using a molecular weight cut-off filter (30 kDa, Millipore), spun at 3600 rpm for twenty minutes. Results Conclusions The FDA-cleared free phenytoin assay is suitable for use in the clinical laboratory producing similar results to our LDT. Switching to the FDA-cleared assay reduces the regulatory burden and eliminates the need for transferring reagent into open channel cassettes and manual dilutions.

Development of an HPLC method using relative molar sensitivity for the measurement of blood concentrations of nine pharmaceutical compounds

We developed a reliable high-performance liquid chromatographic analysis method using a relative molar sensitivity (RMS) technique that does not require an authentic, identical reference analyte material to quantify blood serum carbamazepine, phenytoin, voriconazole, lamotrigine, meropenem, mycophenolic acid, linezolid, vancomycin, and caffeine levels for routine blood concentration measurements. Carbamazepine and caffeine were also used as non-analyte reference materials to calculate the RMS of each analyte. The RMS was calculated from the ratio of the slope of the calibration equation (analyte/non-analyte reference material), then used to quantify analytes in control serum samples spiked with carbamazepine, phenytoin, voriconazole, meropenem, mycophenolic acid, linezolid or vancomycin. In addition, the concentrations of these six drugs in control serum samples determined by the proposed RMS method agreed well with that obtained using a conventional method. The proposed RMS method is a promising tool for the clinical determination of nine drugs, given the accuracy, precision, and efficiency of quantifying these analytes.

Development of UPLC–MS/MS method for the simultaneous quantification of valproic acid and phenytoin in human plasma and application to study pharmacokinetic interaction in epilepsy patients

Valproic acid and phenytoin are two prevalent antiepileptic medications known for their narrow indices and propensity for cardiovascular and respiratory system toxicity. Therefore, therapeutic drug monitoring (TDM) of valproic acid (VAL) and phenytoin (PHE) concentrations in patient plasma is extremely beneficial for improving clinical choices, avoiding adverse reactions, and optimizing treatment for individual patients. In this study, a rapid and sensitive ultra-performance liquid chromatographic tandem mass spectrometer (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of valproic acid (VAL) and phenytoin (PHE) in human plasma. Negative electron spray ionization (ESI-) mode with selective ion recording (SIR) was employed to determine the transitions of m/z 142.98 and m/z 250.93 for VAL and PHE, respectively. The internal standard (IS) betamethasone (BETA) was ionized using positive electron spray ionization (ESI+) and detected by multi-reaction monitoring (MRM) mode to obtain precursor ions and specific fragment ions for quantification, and the MRM transition was chosen to be m/z 393.17 → 355.16. The separation was performed using a Phenomenex Synergi Hydro-RP (4 μm, 250 × 4.6 mm, I.D.) with an isocratic mobile phase consisting of acetonitrile – water (75:25, v/v) at a flow rate of 0.8 mL/min. The column temperature was maintained at 25 °C. The lower limit of quantification of VAL and PHE was 3.6 μg/mL and 0.72 μg/mL, respectively, which resulted in a recovery of more than 85 % for most analytes. According to US-FDA bioanalytical technique validation, the specificity, intra- and inter-day precision and accuracy, matrix effect, carryover, dilution, and stability of all analytes were within acceptable ranges. This analytical method was successful in evaluating the levels of valproic acid and phenytoin in human plasma from epileptic patients.

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.

Tacrolimus and Cyclosporin Pharmacotherapy, Detection Methods, Cytochrome P450 Enzymes after Heart Transplantation.

Advances in organ transplantation were made after the discovery of the pure form of cyclosporine by Dr Jean Borel in the 1970s. In fact, in clinical practice achieving a delicate balance in circulating immunosuppressive necessitate focus on the difficult task of posttransplant therapeutic drug monitoring. The purpose of this study was to determine the pharmacologic properties of cyclosporine- tacrolimus, detection methods, and the effects on the activity of cytochrome P450 enzymes when prescribing the most efficient treatments in forms of polypharmacy for the recipients of heart transplantation. Scientific literature on the interactions of tacrolimus and cyclosporine with human cytochrome P450 enzymes was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/), Web of Science, and Scopus. Prescription immunosuppressive drugs based on polypharmacy accompanied by induction agents could result in hidden neurotoxicity and nephrotoxicity. A literature search shows that cyclosporine prescription with antihypertensives drugs needs close monitoring. Co-administration of tacrolimus and diltiazem or verapamil needs a decrease in the tacrolimus dose by 20-50%. Vigilant attention to the lowest possible statin dose is needed when coadministered with fluvastatin or pravastatin. Polypharmacy based on ticlopidine, clopidogrel, and cyclosporine or tacrolimus needs monitoring of immunosuppressive drug levels for several months. A prescription with clotrimazole or fluconazole needs close monitoring, and itraconazole or ketoconazole needs to reduce the initial dose by 50%. Combination with nefazodone needs to be avoided, and alternative drugs such as sertraline or citalopram could be prescribed in addition to further monitoring consideration. In prescription with phenytoin, the bound and free phenytoin levels need close monitoring. Polypharmacy based on tacrolimus or cyclosporine needs vigilant therapeutic drug monitoring due to the cytochrome P450 enzymes associated with biochemical variables in metabolic pathways. Further attention to polypharmacy should be given to circulate drugs that could hide pharmacokinetics interactions associated with infections, malignancies, chronic kidney disease, and rejection after organ transplantation.

To Study Perioperative Changes in Plasma Phenytoin Levels in Patients with Brain Tumor Undergoing Craniotomy and Its Correlation with Postoperative Seizures

Abstract Introduction Phenytoin, although commonly used for postoperative seizure prophylaxis, exhibits variable results in mitigating seizure frequency following craniotomy. These discrepancies may be linked to a reduction in plasma phenytoin levels subsequent to the surgical intervention. Aims This prospective study aims to characterize changes in plasma phenytoin levels after craniotomy and their relationship with intraoperative blood loss. Methods Fifty consecutive patients were enrolled in this study after obtaining written informed consent. These patients had either been on oral phenytoin for at least 7 days or had received an intravenous loading dose before undergoing craniotomy. Serum phenytoin levels were measured 24 hours preoperatively, immediately before craniotomy (prior to skin incision), postcraniotomy (after skin closure), and 24 hours postcraniotomy. Additionally, intraoperative blood loss was calculated using a modified Gross formula. Results Immediately following craniotomy, there was a statistically significant mean decline of 28.16% in serum phenytoin levels. Furthermore, the analysis revealed a robust positive correlation between the decrease in phenytoin concentration level and several factors, including blood loss during surgery, the duration of the surgical procedure, intravenous fluids administered during surgery, and the occurrence of postoperative seizures. Conclusion This study underscores the potential utility of routinely measuring perioperative serum phenytoin levels in high-risk patients to prevent postcraniotomy seizures. Moreover, it suggests that patients with substantial intraoperative blood loss may benefit from an additional bolus dose of phenytoin toward the end of the surgical procedure.

Assessing risk factors associated with breakthrough early post-traumatic seizures in patients receiving phenytoin prophylaxis.

Post-traumatic seizure (PTS) is a well-known complication of traumatic brain injury (TBI). The objective of this study was to identify risk factors associated with breakthrough early PTS in TBI patients receiving phenytoin prophylaxis. This was a single-centered retrospective study including adult patients admitted to the intensive care unit (ICU), had a TBI, and started on phenytoin for seizure prophylaxis within 24 h of admission. The primary outcome was the incidence and factors associated with early PTS, defined as a confirmed seizure on a continuous electroencephalogram within 7 days of TBI. Secondary outcomes included the association between early post-traumatic seizures and ICU length of stay, hospital length of stay, and in-hospital mortality. A total of 105 patients were included in the final analysis. Patients with early PTS were older (65 vs. 48 years old, p = 0.01), had a higher Marshall score (5 vs. 2, p = 0.01), were more likely to have a Marshall score > 2 (73 vs. 37%, p = 0.01), and had more neurosurgeries for hematoma evacuation (57 vs. 19%, p = 0.01). In patients with early PTS, 57% had a level at the time of seizure, and of those, 87.5% had a therapeutic level (>10 mcg/mL). Patients with early PTS had a longer ICU length of stay (14.7 vs. 5.9 days, p = 0.04) and a greater proportion of hospital mortality (21 vs. 2%, p = 0.02). Patients with higher age, Marshall score, and neurosurgical procedures for hematoma evacuation had higher incidences of breakthrough early PTS despite the use of phenytoin prophylaxis. The majority of patients with early PTS had therapeutic phenytoin levels at the time of seizure when a level was available; however, approximately half (43%) did not have a level.

Seizure Prophylaxis in Young Patients Following Traumatic Brain Injury.

Phenytoin is one of the commonly used anti.seizure medications in nontraumatic seizures. However, its utility and safety in young patients with traumatic brain injury (TBI) for the prevention of early-onset seizures (EOS) are debatable. We sought to explore the use of phenytoin as a seizure prophylaxis following TBI. We hypothesized that administering phenytoin is not effective in preventing EOS after TBI. This was a retrospective observational study conducted on adult TBI patients. EOS was defined as a witnessed seizure within a week postinjury. Data were compared as phenytoin versus no-phenytoin use, EOS versus no-EOS, and among TBI severity groups. During 1 year, 639 TBI patients were included with a mean age of 32 years; of them, 183 received phenytoin as seizure prophylaxis, and 453 received no prophylaxis medication. EOS was documented in 13 (2.0%) patients who received phenytoin, and none had EOS among the nonphenytoin group. The phenytoin group was more likely to have a higher Marshall Score (P = 0.001), lower Glasgow Coma Scale (GCS) (P = 0.001), EOS (P = 0.001), and higher mortality (P = 0.001). Phenytoin was administrated for 15.2%, 43.2%, and 64.5% of mild, moderate, and severe TBI patients, respectively. EOS and no-EOS groups were comparable for age, gender, mechanism of injury, GCS, Marshall Score, serum phenytoin levels, liver function levels, hospital stay, and mortality. Multivariable logistic regression analysis showed that low serum albumin (odds ratio [OR] 0.81; 95% confidence interval [CI] 0.676.0.962) and toxic phenytoin level (OR 43; 95% CI 2.420.780.7) were independent predictors of EOS. In this study, the prophylactic use of phenytoin in TBI was ineffective in preventing EOS. Large-scale matched studies and well-defined hospital protocols are needed for the proper utility of phenytoin post-TBI.

Evaluation of the clinical and quantitative performance of a practical HPLC-UV platform for in-hospital routine therapeutic drug monitoring of multiple drugs

BackgroundIn-hospital therapeutic drug monitoring (TDM) requires a suitable quantification method for target drugs from the viewpoint of precision, throughput, and testing costs. We previously developed a practical HPLC-UV platform for quantification of serum levels of various drugs. In this report, the platform was effectively applied to the quantification of patient serum levels of five different drugs by clinical professionals in our hospital during their daily work.MethodsThe residual sera of patients receiving carbamazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), vancomycin (VCM), or voriconazole (VRCZ) were used in the present clinical study. The quantification method for each drug consisted of rapid solid-phase extraction (SPE) of each drug in the patient serum, followed by optimized HPLC-UV analysis of the drug in the SPE eluate. Furthermore, patient serum levels of PHT, CBZ, and VCM were also measured by ligand-binding assay using a cobas® analyzer in our hospital, and those of LTG and VRCZ were measured by HPLC-MS/MS at an outsourced provider. Passing–Bablok regression analysis and Bland–Altman analysis were employed to analyze the agreement of drug levels in patient sera, which was separately quantified using two different methods—our HPLC-UV platform and the cobas analyzer, or HPLC-UV and HPLC-MS/MS.ResultsAll analytical conditions of the present method using our HPLC-UV platform were well optimized for each target drug quantification in the patient’s serum, and the quantification method for each drug was fully validated for accuracy, precision and reproducibility. Furthermore, Passing–Bablok regression analysis and Bland–Altman analysis revealed that patient serum levels of PHT, CBZ, and VCM quantified by our HPLC-UV platform were closely correlated with those quantified by the cobas® analyzer, and the levels of LTG and VRCZ quantified by our HPLC-UV platform were also correlated with those quantified by HPLC-MS/MS.ConclusionsOur HPLC-UV platform can be performed without requiring special analytical techniques. This platform is expected to be used for the measurement of blood levels of multiple drugs for in-hospital routine TDM.

Phenytoin-induced dyskinesia: a case report

BackgroundDyskinesia is a movement disorder categorized by involuntary movement of muscle. Although dyskinesia can be brought on by taking medications, it can also be a symptom of a variety of diseases. Antiepileptic drug-induced involuntary movements have been well researched. Rare reports have been made for dyskinesia, a type of dystonia caused by phenytoin. The mechanism of its occurrence must be succinctly studied.Case presentationA 53-year-old Asian patient taking phenytoin (100 mg twice daily) experienced symptoms of perioral muscle involuntary movement, impaired speech, and generalized tremors and was admitted to the hospital. Brain magnetic resonance imaging showed significant development of encephalomalacia and porencephaly. The serum phenytoin levels were in the toxic range (33 g/ml). These were suggestive of phenytoin-induced dyskinesia. Levetiracetam and clonazepam were initiated, and the patient showed significant improvement in the symptoms.ConclusionThis case presented a substantial reference value for the differential diagnosis and treatment prognosis of phenytoin-induced dyskinesia. The phenytoin-induced dyskinesia in this patient was successfully reversed with prompt identification and treatment. According to the case study’s findings, such people may benefit from periodic therapeutic drug monitoring.

Evaluation of Goal Phenytoin Levels After an Initial Intravenous Loading Dose at an Academic Medical Center.

Phenytoin intravenous loading doses are administered in status epilepticus to rapidly achieve therapeutic levels. Accurately assessing phenytoin levels after the initial load can be challenging because of its complex pharmacokinetic profile and nonstandardized weight-based loading doses. The objectives of this analysis were to determine the incidence of patients achieving goal phenytoin levels after the initial loading dose and characterize factors that contribute to achieving the goal level. This single-center, retrospective cohort analysis was approved by our institutional review board and included adult patients who received a phenytoin load from May 2016 to March 2021. Patients were excluded if no total phenytoin level was drawn within 24 hours of the load, if the maintenance dose was given before the first level was drawn, or if the patient was on phenytoin before the load. The major endpoint was the percentage of patients achieving a corrected goal phenytoin level of ≥10 mcg/mL after the initial load. Multivariate regression was used to determine predictors of achieving the goal phenytoin level. Of the 152 patients included, 139 patients (91.4%) achieved a corrected goal level after the first load. Patients at goal received a significantly higher median weight-based loading dose (19.1 mg/kg [15.0-20.0] vs 12.6 mg/kg [10.1-15.0], P < 0.01). The multivariate analysis identified weight-based dosing as a statistically significant predictor of achieving the corrected goal level (odds ratio, 1.30; 95% CI, 1.12-1.53; P < 0.01). Most patients achieved a corrected goal phenytoin level after the initial load. A higher median weight-based loading dose was shown to be a predictor of achieving the goal level and should be encouraged for rapid seizure termination. Future studies are warranted to confirm patient-specific factors that affect rapid achievement of the goal phenytoin level.

Effect of Cyclooxygenase Inhibition on P-Glycoprotein Expression and Phenytoin Level in Brain Tissue of Pilocarpine Induced Epilepsy in Rats

Effect of Cyclooxygenase Inhibition on P-Glycoprotein Expression and Phenytoin Level in Brain Tissue of Pilocarpine Induced Epilepsy in Rats

Interaction of Phenytoin with Enteral Formulas, Proteins, and Dietary Fiber in Vitro and in Vivo

Simultaneous administration of enteral formula and phenytoin in the clinical setting is known to reduce the plasma concentration of phenytoin. In this study, we examined the binding of phenytoin with enteral formulas and its components by quantifying the free phenytoin concentration. Furthermore, we investigated the effect of enteral formulas on gastrointestinal absorption of phenytoin in rats. The free phenytoin rate was reduced in vitro when phenytoin and enteral formula or pectin, a dietary fiber in enteral formulas, were co-administered. In vivo, when phenytoin and the enteral formula Mei Balance R® were co-administered, the time to maximum plasma concentration (Tmax) after oral administration was significantly increased. Moreover, the area under the phenytoin concentration-time curve from time zero to 6 h (AUC0-6 h) was significantly increased by co-administration of phenytoin with the enteral formula PG Soft EJ®. These results showed the gastrointestinal absorption of phenytoin differs according to the type of enteral formula. In addition, we found the first time that plasma phenytoin levels increase when combined with enteral formula. Among the components of enteral formulas, in particular, milk protein delayed the absorption of phenytoin. Moreover, milk protein, casein and carrageenan tended to increase AUC0-6 h. These results suggest the change in phenytoin concentration is due not only to the binding of enteral formula but also to the disintegration of components such as protein. Therefore, when co-administrated of phenytoin and enteral formula, phenytoin must be monitored frequently according to the enteral formula interaction.

Development of volumetric absorptive microsampling for analysis phenytoin levels and its application to monitoring therapy in epilepsy patients

Development of volumetric absorptive microsampling for analysis phenytoin levels and its application to monitoring therapy in epilepsy patients

Phenytoin Toxicity with High Dose, Concomitant Ascorbic Acid Dosing.

High dose ascorbic acid may increase risk of phenytoin toxicity. This case report demonstrates high phenytoin levels resulting in adverse drug reactions subsequent to dosing concomitantly with high dose vitamin C, or ascorbic acid (AA), as a precaution against acquiring corona virus (COVID) infection. This patient suffered from a major seizure when he ran out of his phenytoin prescription. Subsequent initiation of phenytoin and later addition of high dose AA resulted in truncal ataxia and falls with bilateral wrist and finger extension weakness. Phenytoin and AA were discontinued, and the patient returned to baseline on a new medication regimen of lacosamide and gabapentin without any other major seizures one year later.

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 &amp;lt; 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.

Phenytoin as seizure prophylaxis in hematopoietic stem cell transplantation with busulfan conditioning.

BackgroundPhenytoin is widely used as primary seizure prophylaxis in hematopoietic stem cell transplantation in patients undergoing myeloablative conditioning with busulfan. Because of the negative side effects of phenytoin, we abandoned phenytoin use in these patients. To assess the effect of this change, we performed a retrospective cohort study on all patients receiving busulfan.MethodsWe included 139 patients who underwent conditioning with busulfan for hematopoietic stem cell therapy. We registered the use of phenytoin, as well as the occurrence of seizures, until 7 days after busulfan administration. We compared seizure incidence between patients who received phenytoin and those who did not.ResultsOf the 43 patients who received phenytoin prophylaxis, four patients (9.3%) had a seizure during the conditioning regimen, of which two patients had cerebral non-Hodgkin lymphoma. Furthermore, all these 4 patients had very high levels of phenytoin (intoxication). Of the 96 patients that did not receive phenytoin prophylaxis, three patients (3.1%) had a seizure, and one of these patients had an undefined cerebral lesion. Phenytoin did not relate to seizure prevention in a logistic regression analysis.ConclusionWe conclude that phenytoin prophylaxis in patients treated with busulfan is obsolete and possibly harmful, as phenytoin intoxication can occur. We recommend discontinuing the use of phenytoin as primary seizure prophylaxis in these patients.

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.

Evaluation of phenytoin loading doses in overweight patients using actual versus adjusted body weight

Background and ObjectivesThe appropriate loading dose strategy for phenytoin/fosphenytoin in overweight patients is unknown. A small pharmacokinetic study indicated that overweight patients have a higher volume of distribution and potentially would benefit from using adjusted body weight (AdjBW) instead of actual body weight (ABW) to calculate the loading dose. The purpose of this study was to determine the optimal loading dose strategy of phenytoin in patients whose ABW is greater than 120% of their ideal body weight (IBW) using either ABW or AdjBW for calculation of the loading dose. MethodsThis was a single center, retrospective study which included patients who received a loading dose of phenytoin of at least 10 mg/kg based on ABW, had a phenytoin level drawn <6 h after the end of the dose, and weighed ≥120% of their IBW. Patients were excluded if they received intramuscular phenytoin or fosphenytoin or were prescribed phenytoin prior to the loading dose. Patients were divided into two groups, those who were dosed using their AdjBW versus those dosed using ABW. The primary outcome was achievement of therapeutic phenytoin level of 10–20 mcg/mL. Secondary outcomes included achievement of a subtherapeutic or supratherapeutic level. ResultsA total of 195 patients (128 in AdjBW group and 67 in ABW group) met criteria for inclusion. Patients in the AdjBW group weighed more (96.2 kg vs. 91.2 kg, p = 0.04) and received a lower dose in milligrams (1364 vs. 1760, p < 0.0001) and in mg/kg of ABW (14.2 vs. 19.3, p < 0.0001). The primary outcome was achieved in 74% of patients in the AdjBW group and 57% of patients in the ABW group (p = 0.02). Patients in the ABW group were more likely to have a supratherapeutic level (43% vs. 22%, p = 0.003), although adverse reactions did not differ between the groups. DiscussionPatients weighing >120% of their IBW (average body mass index 33.5 kg/m2) who received a 20 mg/kg loading dose based on AdjBW were more likely to achieve a therapeutic phenytoin concentration compared to those dosed based on ABW. Further research is needed to correlate this finding with clinical outcomes, such as resolution of status epilepticus.

Characteristics and Consequences of Medication Errors in Pediatric Patients Reported to Ramathibodi Poison Center: A 10-Year Retrospective Study.

PurposeThis study was performed to evaluate the clinical characteristics of, consequences of, and factors associated with medication errors (MEs) that cause harm to pediatric patients (<15 years of age) treated in the hospital setting.Patients and MethodsWe performed a 10-year retrospective study (January 2011–December 2020) by analyzing data from the Ramathibodi Poison Center. MEs were classified into categories A to I according to the severity of the outcome.ResultsIn total, 121 patients were included in the study. Most (51.24%) patients were male. Their median age was 1 year (range, 1 hour–14 years). Infants, newborns, and toddlers were the three most common age groups in which MEs were reported. Most MEs occurred during the afternoon shift [n = 60 (49.59%)] and in the inpatient department (66.12%). The most common type of MEs was a dose error (64.46%). Antibiotics, sedative agents, and bronchodilators were the three most common classes of ME drugs. Four patients died. Three deaths occurred because of a dose error. One patient was a 1-year-old girl who received an iatrogenic intravenous phenytoin overdose of 10 times the normal dose, resulting in a phenytoin level of 72.4 mcg/mL. She died 22 hours after the ME occurred. The work shift was the only factor that significantly differed between patients with category C and D MEs and those with category E to I MEs.ConclusionSmall children were at highest risk for MEs. MEs induced harm and deaths in some patients. A preventive and safety system, including appropriate shift work administration, should be emphasized and implemented to prevent and/or decrease the occurrence of MEs.