Fosphenytoin Research Articles

Comparison of pharmacokinetics and safety between CE-fosphenytoin sodium, fosphenytoin sodium, and phenytoin sodium after intravenous and intramuscular administration in healthy volunteers.

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400mg PE) or R1 (400mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

1010: IMPACT OF USP-800 ON ADMINISTRATION TIMES OF HAZARDOUS INTRAVENOUS ANTIEPILEPTIC MEDICATIONS

Introduction: USP general chapter < 800> establishes comprehensive guidelines for safe handling of hazardous drugs, including some antiepileptics, by healthcare personnel. This guidance increases the number of steps required to safely compound and deliver medications, potentially resulting in a delay of care for time-sensitive medications. The aim of this study is to assess the impact that implementation of USP < 800> had on the timeliness of administration of antiepileptic medications at an academic medical center. Methods: A single center, retrospective study of time from verification to administration pre- and post-USP < 800> implementation of adult one-time orders of intravenous (IV) fosphenytoin (FOS), phenytoin (PHT), and valproic acid (VPA) was conducted. The study period includes 10 months immediately prior to adoption of USP < 800> and five months post adoption. One-time orders were included if scheduled administration time was within 90 minutes of verification. The primary outcome was time in minutes from order verification to medication administration. Subgroup analyses compared the results based on method of medication delivery (pneumatic tube system (PTS) vs hand delivery) and if orders were designated as “STAT”. Results: A total of 248 orders met inclusion criteria: 33 FOS, 12 PHT, and 203 VPA, (pre: 176, post: 72). Time from verification to administration was 15 minutes longer in the post-implementation group for aggregate antiepileptic orders (54 [35-72] vs 69 [48-90], p=0.0013). This increase in time to administration post-implementation was comparable across each of the medications assessed. Subgroup analysis of orders marked as “STAT” showed a similar increase in median time to administration (43 [28-65] vs 56 [34-86], p=0.0406). There was no difference in time to administration comparing PTS to hand delivery (71 [46-109] vs 68 [51-88], p=0.6603). Conclusions: Implementation of USP < 800> increased the median time from order verification to administration for three hazardous IV antiepileptic medications. In patients with status epilepticus, a 15 minute delay could prolong time to seizure termination resulting in worse clinical outcomes. Institutions will need to develop alternative methods for compounding and delivery to ensure timely administration while maintaining safety.

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial

ObjectiveStatus epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy,...

A critical review of fosphenytoin sodium injection for the treatment of status epilepticus in adults and children

ABSTRACT Introduction Status epilepticus (SE) is a neurological emergency that can occur in patients with or without epilepsy. Rapid treatment is paramount to mitigate risks of neuronal injury, morbidity/mortality, and healthcare-cost burdens associated with SE. Fosphenytoin is the prodrug of phenytoin designed to enable faster administration and improved tolerability as compared to intravenous (IV) phenytoin in the treatment of SE. Areas covered This review evaluates the chemistry, pharmacokinetics, pharmacodynamics, safety, and tolerability of fosphenytoin. Efficacy data for fosphenytoin in the treatment of SE in adults and children are analyzed from initial phase I trials in 1988 through current phase III trials, including the Established Status Epilepticus Treatment Trial (ESETT). Expert opinion IV phenytoin is an established treatment of SE, but its alkaline aqueous vehicle is associated with dermatologic irritation and systemic complications when rapidly infused. The water-soluble nature of its prodrug, fosphenytoin, allows for rapid infusion, and it is rapidly converted to phenytoin when administered intravenously or intramuscularly. In the ESETT, IV fosphenytoin demonstrated similar efficacy in treatment of established SE when compared to IV levetiracetam and IV valproate in adults and children, making it a reasonable choice in the treatment of SE that is unresponsive to benzodiazepines.

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

Prise en charge des états de mal épileptiques en préhospitalier, en structure d’urgence et en réanimation dans les 48 premières heures (à l’exclusion du nouveau‑né et du nourrisson)

La Société de réanimation de langue française et la Société française de médecine d’urgence ont décidé d’élaborer denouvelles recommandations sur la prise en charge de l’état de mal épileptique (EME) avec l’ambition de répondre leplus possible aux nombreuses questions pratiques que soulèvent les EME : diagnostic, enquête étiologique, traitementnon spécifique et spécifique. Vingt‑cinq experts ont analysé la littérature scientifique et formulé des recommandationsselon la méthodologie GRADE. Les experts se sont accordés sur 96 recommandations. Les recommandations avecle niveau de preuve le plus fort ne concernent que l’EME tonicoclonique généralisé (EMETCG) : l’usage des benzodia‑zépines en première ligne (clonazépam en intraveineux [IV] direct ou midazolam en intramusculaire) est recommandé,répété cinq minutes après la première injection (à l’exception du midazolam) en cas de persistance clinique. En casde persistance cinq minutes après cette seconde injection, il est proposé d’administrer la deuxième ligne thérapeu‑tique : valproate de sodium, (fos‑)phénytoïne, phénobarbital ou lévétiracétam. La persistance avérée de convulsions30 minutes après le début de l’administration du traitement de deuxième ligne signe l’EMETCG réfractaire. Il est alorsproposé de recourir à un coma thérapeutique au moyen d’un agent anesthésique intraveineux de type midazolam oupropofol. Des recommandations spécifiques à l’enfant et aux autres EME sont aussi énoncées.

Identification, Synthesis, Characterization and Quality Control Strategy of New Process-Related Impurities in Fosphenytoin Sodium

Fosphenytoin sodium is a water dissolvable phenytoin prodrug that is directed intravenously to convey phenytoin, conceivably more securely than intravenous phenytoin. It is most ordinarily utilized in the intense treatment of convulsive status epileptics. The examination of the procedure-related contaminants will not help exclusively to advance the process parameters yet additionally to create sensible analytical methods and set the quality standard for a quality control system in pharmaceutical manufacturing. During the production of fosphenytoin sodium, all the process-related impurities are controlled in every stage and three degradation impurities are managed in the final API as per USP monograph. Besides, five unknown and one known contaminants were detected by HPLC method. All these impurities were identified, synthesized, isolated and characterized by IR, 1D-NMR (1H, 13C, DEPT) and HRMS spectral techniques. The mechanism of the formed impurities is examined for the first time. Quality control procedures to manage these impurities were developed to acquire the mass medication of ICH grade quality.

Lessons from the Established Status Epilepticus Treatment Trial

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design.This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures"

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

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

Fosphenytoin population pharmacokinetics in the acutely ill pediatric population

目的 了解儿童磷苯妥英药代动力学 设计 回顾性群体药代动力学分析场所 一家大型三级儿童医院的急诊或PICU 对象 2011年1月至2017年6月于急诊或PICU接受抗惊厥治疗的19岁以下患儿。干预措施 采用NONMEM v7.2进行群体药代动力学分析。通过模拟试验确定最佳负荷剂量及维持剂量。 测量方法及主要结果 共536例患儿符合研究标准(55.4%男性，中位年龄3.4岁，IQR 0.92-8.50)。中位磷苯妥英用量15.1 mg/(kg·次)(IQR 6.3～20.7)。单次给药后4.2(IQR 2.5～7.8)h平均血清含量(17.5±7.8)mg/L。按无脂体重计算所有参数并测算血清肌酐及协同使用苯巴比妥对清除率的影响后，建立的二室药代动力学模型最为适用。模拟试验证实按20 mg/kg负荷并继以6 mg/(kg·次)，每8小时1次的方式给药时，血药浓度达10～20 mg/L范围比例最高，肾功能减退患儿达到治疗目的所需剂量减低。 结论 基于无脂体重建立的20 mg/kg负荷继以6 mg/(kg·次)，每8小时1次是合理的经验性给药策略，可达到并维持治疗谷浓度。联合使用苯巴比妥可能增加苯妥英清除，肾功能减退患儿应减少磷苯妥英用量。

Fosphenytoin pre-medication for pediatric extra-operative electrical stimulation brain mapping

PurposeWe studied the effect of fosphenytoin (FOS) pre-medication on the incidence and thresholds of after-discharges (ADs), seizures, and functional responses during electrical stimulation mapping (ESM). MethodsAs individualized by the attending epileptologist, FOS was given intravenously at 2 mg-phenytoin-equivalents (PE)/kg/min or 150 mg-PE/min (whichever slower). Patients who received and did not receive FOS were compared for the incidence and thresholds of ADs, seizures, and functional responses. ResultsBefore ESM, 40 and 82 patients respectively were pre-medicated/not pre-medicated with FOS. The incidence of ESM-induced seizures was significantly lower in FOS pre-medicated patients (22.5% vs. 42.7%, p = 0.044), whereas temporal language threshold was higher (9.2 vs. 6.5 mA, p = 0.032). FOS was more efficacious in preventing ESM-induced seizures in patients with symptomatogenic zone ipsilateral to the side of ESM.Although FOS dose had no significant effect on minimum language, minimum motor, or AD thresholds; seizure and temporal language thresholds showed trends approaching significance, intersecting at 12.2 mg-PE/kg. The incidence of ESM-induced seizures was significantly lower in those who received FOS at a dose of ≤12 mg/kg (9.1%) compared to those who did not receive any FOS (42.7%, p = 0.046), while the temporal language thresholds were not significantly different (6.3 vs. 6.5 mA, p = 0.897). ConclusionsThis study provides class III evidence that FOS pre-medication before ESM decreases the incidence of ESM-induced seizures, but increases temporal language threshold. FOS pre-medication may thus be considered before ESM. Future studies should prospectively verify these observations and characterize dose-response relationships.

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

PurposeDue to the complex pharmacokinetic profiles of phenytoin (PHT) and fosphenytoin (FOS), achieving sustained, targeted serum PHT levels in the first day of use is challenging. MethodsA population based approach was used to analyze total serum PHT (tPHT) level within 2–24h of PHT/FOS loading with or without supplementary maintenance or additional loading doses among PHT-naïve patients in the acute hospital setting. Adequate tPHT serum level was defined as ≥20μg/mL. ResultsAmong 494 patients with 545 tPHT serum levels obtained in the first 2–24h after the loading dose (LD), tPHT serum levels of either <or≥20μg/mL were observed along wide and overlapping cumulative dose ranges. Among those receiving 15–20mg/kg and 20–55mg/kg weight-based loading dose, 63% and 51% respectively did not attain tPHT serum level of ≥20μg/mL even within the first 6h of treatment. For the 393 available concomitant free and total serum PHT levels, correlation was weak, r=0.36. ConclusionClose laboratory surveillance and PHT/FOS dose adjustments are recommended to ensure adequate and sustained tPHT serum levels early in treatment. Free serum PHT level is the preferred method of drug monitoring.

New precautions for fosphenytoin product in EU

New precautions for fosphenytoin product in EU

Posterior reversible encephalopathy syndrome in a patient with Bickerstaff's brainstem encephalitis

AbstractBackgroundBickerstaff's brainstem encephalitis (BBE) is characterized by acute ophthalmoplegia, ataxia and impaired consciousness. Serum anti‐GQ1b antibody in the acute phase has been detected in many BBE cases. Posterior reversible encephalopathy syndrome (PRES) is characterized by acute neurological symptoms with vasogenic edema in the bilateral parieto‐occipital regions. It has been pointed out that the activation of inflammatory cytokines might be involved in the pathophysiology of PRES and BBE.Case presentationA 37‐year‐old woman had an upper respiratory infection a week before losing consciousness. On admission, she was in a coma and her blood pressure was 134/96 mmHg. Doll's eye phenomenon was negative. Bilateral tendon reflexes were normal, although Babinski signs were bilateral positive. Cerebrospinal fluid examination showed normal protein concentration and cell counts. Brain magnetic resonance imaging findings were normal. We administered intravenous methylprednisolone therapy (1000 mg/day), acyclovir (1500 mg/day) and fosphenytoin sodium hydrate (22.5 mg/kg/day). Brain magnetic resonance imaging on the third admission day showed an increased apparent diffusion coefficient map, and high intensities in diffusion‐weighted imaging in the bilateral occipital cortex and subcortex, which are consistent with PRES. Nerve conduction studies were normal. The patient was treated with intravenous immunoglobulin therapy (0.4 g/kg/day) from the fourth admission day. Her consciousness level rapidly improved, and we were able to detect obvious ophthalmoplegia and limb ataxia. Diffusion‐weighted imaging was improved on the 13th day of admission. Serum anti‐GQ1b immunoglobulin G antibody on admission was positive. We ultimately diagnosed her with BBE.ConclusionsWe reported a rare case of BBE complicated with PRES.

Incidence and risk factors of hypotension after intravenous fosphenytoin administration.

Fosphenytoin (FOS) administered intravenously offers several benefits over intravenously administered phenytoin, including a faster infusion rate, decreased pain and irritation at the infusion site, and fewer cardiovascular complications. However, some studies suggest that the intravenous administration of FOS in some patients may also induce adverse cardiovascular events. Here, we investigated the clinical characteristics of patients who experienced hypotension following an intravenous infusion of a FOS loading dose. We reviewed the medical records of consecutive patients who received an intravenous (IV) dose of FOS between July 2013 and June 2015. Various clinical and demographic parameters were analysed, including comorbidities, drug history, seizure aetiology and type, incidence of hypotension/cardiac arrhythmia and the dosing data (ie the total dose, concentration and FOS IV infusion rate). Hypotension was defined as a ≥20mm Hg decrease in systolic blood pressure or a ≥10mm Hg decrease in diastolic blood pressure during or after FOS IV infusion. These parameters were compared between patients with and without hypotension. Of the 28 included patients, 11 (39%) had hypotension associated with an IV infusion of FOS, two of whom also had an atrioventricular block. Most patients (22/28, 79%) who received an IV infusion of FOS had status epilepticus (SE). The presence of SE was significantly associated with the development of hypotension (P=.026); hypotension occurred in half of the patients with SE, but did not occur in six patients without SE. Hypotension was also associated with old age (≥60years, P=.034) and the presence of a systemic infection (P=.04). Our study shows that hypotension associated with an IV infusion of FOS is not a rare adverse event, especially in patients with SE. Moreover, we found that old age and the presence of a systemic infection increased the risk of hypotension. These findings suggest that FOS should be infused under careful cardiovascular monitoring, especially in patients who are at higher risk of developing hypotension.

Development and application of an ex vivo fosphenytoin nasal bioconversion/permeability evaluation method

There is an increasing interest in the intranasal delivery of central nervous system-active drugs due to the existence of a direct nose-to-brain connection. However, poor solubility limits the amount of drug that can be administered within an aqueous solution. In the present work, the objectives were to develop an ex vivo bioconversion/permeability evaluation method and to study the ex vivo bioconversion of the hydrophilic phosphate ester prodrug fosphenytoin (FOS) to the active drug phenytoin (PHT) and their comparative nasal permeation.Bioconversion/permeability studies were performed in excised porcine nasal mucosa mounted in Ussing chambers. The physical integrity of the tissues was evaluated by measurement of the transepithelial electrical resistance (TEER). The simultaneous quantitative assay of FOS, PHT and its major metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) was developed and validated according to international guidelines using a liquid chromatography analytical method. The FOS bioconversion rate and PHT and FOS apparent permeability coefficients (Papp) were determined at different time points. FOS bioconversion was also qualitatively investigated in human nasal mucus.The developed liquid chromatography method combines a fast and inexpensive sample preparation with inactivation of the enzymatic metabolism of the prodrug during sample manipulation and storage. It was linear, precise, accurate, and presented a high analyte recovery. FOS was converted ex vivo to PHT but the metabolite HPPH was not detected. The bioconversion rate increased with FOS concentration and with time, which suggests a diffusion-limited process. FOS was also converted to its active drug by human nasal mucus. A novel mathematical data analysis method was developed to reduce the bias introduced by variable mucosal TEER in the permeability results. At comparable FOS and PHT concentrations the ln(PappPHT) of both compounds showed little difference, which indicates that the use of a hydrophilic and charged prodrug did not hinder overall drug permeation. At the highest tested FOS concentration it was possible to quantify FOS in the receiver chambers, meaning that at a sufficiently high concentration the FOS permeation rate overcame its bioconversion rate. The ln(PappPHT) tended to similar equilibrium values as the assay progressed, but with higher FOS concentrations that equilibrium was attained faster. Acidic pH reduced the permeability of both PHT and FOS.The developed bioconversion/permeability evaluation method will constitute an important tool to select the most promising formulations before proceeding to in vivo studies. Importantly, it allowed the demonstration of phosphatase activity and FOS bioconversion in nasal mucosa, as well as the prodrug's nasal permeation potential. Furthermore, this study demonstrates the possibility of formulating phosphate prodrugs of poorly soluble central nervous system-active drugs as a strategy to increase the solubilized drug doses administered through the nasal route.

Canine status epilepticus treated with fosphenytoin: A proof of principle study.

There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available to treat status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs, with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people. A randomized clinical trial was performed for dogs with CSE. Dogs who presented during a seizure or who had additional seizures after enrolling received intravenous (i.v.) benzodiazepine (BZD) followed immediately by intravenous infusion of 15 mg/kg phenytoin equivalent (PE) of fosphenytoin (FOS) or saline placebo (PBO). If seizures continued, additional AEDs were administered per the standard of care for veterinary patients. Total and unbound plasma phenytoin (PHT) concentrations were measured. Consent was obtained for 50 dogs with CSE. Thirty-one had additional motor seizures and were randomized to the study intervention (22 FOS and 9 PBO). There was a statistically significant difference in the 12 h responder rate, with 63% in the FOS group versus 22% in the placebo group (p = 0.043) having no further seizures. The unbound PHT concentrations at 30 and 60 min were within the therapeutic concentrations for people (1-2 μg/ml) with the exception of one dog. There was mild vomiting in 36% of the FOS group (7/22) within 20 min of FOS administration and none of the placebo group (0/9) (p = 0.064). This proof of concept study provides the first evidence that FOS is tolerated and effective in canine SE at PHT concentrations clinically relevant for human SE. Furthermore, naturally occurring CSE can be utilized as a translational platform for future studies of novel SE compounds.

Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus.

Canine status epilepticus (CSE) has potential as a translational platform to evaluate the safety and efficacy of novel compounds and inform human status epilepticus trials. The aim of this study was to determine the intravenous dose of fosphenytoin (FOS) needed for dogs in a CSE clinical trial to attain phenytoin (PHT) concentrations similar to those used for human status epilepticus and monitor PHT concentrations. Four healthy dogs were used to characterize PHT pharmacokinetics. Each received either 15 mg/kg or 25 mg/kg of PHT equivalent intravenously. Blood samples were collected and FOS (total) and derived PHT (total and unbound) plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Noncompartmental pharmacokinetics (PK) parameter values were determined and compartmental PK modeling and simulations were used to select the dose for the clinical trial with a target goal of 1-2 μg/ml unbound PHT at 30-60 min postinfusion. Predicted total and unbound PHT concentrations were compared with concentrations in blood collected from dogs treated for CSE in the clinical trial. Initial estimates suggested that a loading dose of 25 mg/kg would attain unbound concentrations of 1-2 μg/ml; however, this dose produced concentrations above 3-6 μg/ml, which resulted in clinically significant toxicity. A two-compartment model best fit the PHT concentration data with alpha-phase half-life of 2-5 min and elimination half-life of ~5 h. Based on the simulations, a dose of 15 mg/kg was selected and used in the clinical trial and 15 of 16 dogs randomized to the treatment arm had PHT plasma concentrations within the goal range. This study demonstrates that characterization of pharmacokinetics in a small number of dogs is useful in determining dosage regimens designed to attain targeted concentrations in clinical trials. Using this approach, we were able to determine a safe and effective dose of FOS for a clinical trial of CSE.

Relative Bioavailability of Orally Administered Fosphenytoin Sodium Injection Compared with Phenytoin Sodium Injection in Healthy Volunteers

To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. Open-label, randomized, single-dose, two-period, two-sequence crossover study. University-affiliated clinical research center funded by the National Center of Research Resources. Ten healthy adult volunteers. Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72hours after dose administration. After a 7-14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). The mean age and weight of the 10 subjects were 37years and 72.5kg, respectively, and the mean dose was 5.6mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported. FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted.

ABSTRACT 329

Background and aims: Status Epilepticus (SE) continues to be one of the most common pediatric acute care emergencies. Conventional SE protocols advocate Phenobarbitone as a second line antiepileptic drug (AED) if the child continues to seize even after Benzodiazepine (BZD) and Fosphenytoin (FPE) loading. Aims: We aimed to investigate the efficacy and safety of Levetiracetam as stage two AED in pediatric SE in place of phenobarbitone. Methods: Study design: Prospective observational study All consecutive children admitted to pediatric emergency during the study period (Jan 2012 to Nov 2013) received second stage AED Levetiracetam to control SE were included in the study to describe the safety and efficacy of Levetiracetam. Results: Of 111 children admitted with convulsive SE during the study period, 33 (36.7%) received Levetiracetam as stage two AED to achieve seizure control. Intravenous Levetiracetam at 30 mg/kg over 15 minutes followed by 10 mg/kg/dose as maintenance at 8 hourly interval was administered in all those enrolled. The mean age of presentation was 45.6 months [45.6(20.5–70.7)]. Among those received Levetiracetam, 22 children [67%; 22/33] had first episode seizure presenting as SE and 11 children [33%; 11/33] have had prior history of seizure. Levetiracetam had comparable efficacy (84%) and time to abort SE (16 min) to phenobarbitone as second stage AED without any side effects. Conclusions: This study concludes that Levetiracetam has comparable efficacy to be used as a second line AED in managing convulsive SE in infants and children with better side effect profile.