Fosphenytoin Administration Research Articles

Hemodynamic Effects and QTc Changes with Intravenous Phenytoin and Fosphenytoin during Propofol and Sevoflurane Anesthesia

Abstract Background Phenytoin is a commonly used antiepileptic drug (AED) for postoperative seizure prophylaxis; it is associated with adverse cardiovascular effects. Fosphenytoin is considered a safer alternative but can produce prolongation of QT interval. This hypothesis generating pilot study evaluated the changes in hemodynamics and the heart rate corrected QT interval (QTc) with phenytoin and fosphenytoin during propofol and sevoflurane anesthesia. Methods Eighty American Society of Anesthesiologists I and II patients aged 20 to 60 years undergoing elective supratentorial craniotomy requiring a loading dose of the intraoperative AED for seizure prophylaxis were randomized into four groups: group PP, receiving propofol (0.2 mg/kg/min) for maintenance and phenytoin (15 mg/kg) for seizure prophylaxis; group SP, receiving sevoflurane (1 minimal alveolar concentration) for maintenance and phenytoin(15mg/kg) for seizure prophylaxis; group PF, receiving propofol for maintenance and fosphenytoin (22.5 mg/kg) for seizure prophylaxis; and group SF, receiving sevoflurane for maintenance and fosphenytoin for seizure prophylaxis. The heart rate, systolic, diastolic, mean arterial pressure, and QTc were measured at baseline before anesthesia, during maintenance of anesthesia, and during various phases of AED infusion and up to 1 hour after completion of AED administration. Appropriate statistical analysis was done and a two-tailed p-value of less than 0.05 was considered significant. Results The incidence of changes in the heart rate and hypotension was not significant among the groups. Administration of fosphenytoin significantly prolonged QTc, which was more remarkable when coadministered with sevoflurane than with phenytoin. Conclusion Fosphenytoin did not confer hemodynamic benefits over phenytoin. Fosphenytoin produces prolongation of QTc, and when coadministered with sevoflurane, the prolongation is more significant, suggesting a possible additive effect.

Improving time for administration of second-line antiseizure medications for children with generalized convulsive status epilepticus using quality improvement methodology.

Status epilepticus is a life-threatening neurological emergency. However, delay in median time to administration of second-line antiseizure medication exists. The aim of this quality improvement initiative was to decrease the average delay before fosphenytoin is administered for pediatric patients with generalized convulsive status epilepticus from 30min (baseline data collected in 2013) to 15min (50% reduction) by December 2015 and sustain this for 1year. Our team conducted an analysis of baseline data for patients with continuous generalized convulsive status epilepticus who received fosphenytoin after receiving first-line benzodiazepine treatment. Using quality improvement methodology, areas for improvement were identified and specific interventions developed and implemented. A timeline of 15min to initiate fosphenytoin administration after failure of first-line treatment was considered reasonable and achievable as a project aim. A total of 199 patients were included in the dataset for the project. The database included patients aged 1month and older. Ninety-eight percent of patients were between 1month and 19years of age. The gender distribution was even, with 54% of patients being White or Caucasian, 30% African American or Black, and 16% classified as "other." From January 2014 through December 2019, the average time before initiating fosphenytoin administration after failure of benzodiazepine therapy, for patients with generalized convulsive status epilepticus, decreased from 30min (SD=45.7) to 11.4min (SD=8.2, p=.043), thus reducing time to administration by 62%. Quality improvement methodology can be successfully applied to decrease administration time between first- and second-line antiseizure medications for status epilepticus.

775: Risk Factors for Hypotension Associated With Phenytoin and Fosphenytoin Administration in Adults

Tednes, Patrick1; Rech, Megan1; Moomey, Kyle1; Monzon, Brian1; Donahey, Elisabeth2 Author Information

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.

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.

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

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

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.

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.

Comparative canine Pharmacokinetics–Pharmacodynamics of Fospropofol Disodium Injection, Propofol Eemulsion, and Cyclodextrin-Enabled Propofol Solution Following Bolus Parenteral Administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

Status epilepticus

Status epilepticus (SE) is a medical emergency associated with significant morbidity and mortality. SE is defined as a continuous seizure lasting more than 30 min, or two or more seizures without full recovery of consciousness between any of them. Based on recent understanding of the pathophysiology, it is now considered that any seizure that lasts more than 5 min probably needs to be treated as SE. GABAergic mechanisms play a crucial role in terminating seizures. When the seizure persists, GABA-mediated mechanisms become ineffective and several other putative mechanisms of seizure suppression have been recognized. Early treatment of SE with benzodiazepines, followed if necessary by fosphenytoin administration, is the most widely followed strategy. About a third of patients with SE may have persistent seizures refractory to the first-line medications. They require aggressive management with second-line medications such as barbiturates, propofol, or other agents. In developing countries where facilities for assisted ventilation are not readily available, it may be helpful to use nonsedating antiepileptic drugs (such as sodium valproate, levetiracetam, or topiramate) at this stage. It is important to recognize SE and institute treatment as early as possible in order to avoid a refractory state. It is equally important to attend to the general condition of the patient and to ensure that the patient is hemodynamically stable. This article reviews current knowledge regarding the management of convulsive SE in adults.

XIII. Antiseizure Prophylaxis

XIII. Antiseizure Prophylaxis

Fosphenytoin may cause hemodynamically unstable bradydysrhythmias

The prodrug fosphenytoin (FOS) was recently introduced as an alternative to phenytoin (PTN) and has since become a first line therapy for status epilepticus. Unlike PTN, FOS generally has been considered to be safe from cardiac toxicity. To better characterize cardiac toxicity associated with FOS administration, we performed a review of the Food and Drug Administration’s Adverse Event Reporting System databank for reports of possible FOS toxicity from 1997–2002. There were 29 applicable reports of adverse cardiac events likely related to FOS infusion, including 10 cardiac deaths. Among survivors, there were four cases of high-grade atrioventricular block, and five cases of transient sinus arrest. Our data suggest that FOS may produce more cardiac toxicity than previously thought. Clinicians should consider administering intravenous FOS in a monitored setting for selected high-risk patients.

Hyperphosphatemia due to fosphenytoin in a pediatric ESRD patient

Fosphenytoin is indicated for the treatment of generalized convulsions and seizures occurring during neurosurgery. Metabolites of fosphenytoin include phenytoin, phosphate, and formaldehyde. The drug monograph recommends caution in administering fosphenytoin to patients in whom phosphate restriction is necessary. Additionally, fosphenytoin has altered pharmacokinetics in end-stage renal disease patients. We report a 17-year old African-American male with end-stage renal disease who developed acute hyperphosphatemia to 3.9 mmol/L (12.1 mg/dL) following the intravenous administration of 1000 mg of fosphenytoin for an idiopathic complex partial seizure. To our knowledge, this is the first report of acute hyperphosphatemia due to fosphenytoin administration. Due to this risk of hyperphosphatemia, we recommend that fosphenytoin should be used with caution in the end-stage renal disease population.

Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus.

Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.

A comparison of central brain (cerebrospinal and extracellular fluids) and peripheral blood kinetics of phenytoin after intravenous phenytoin and fosphenytoin

Phenytoin (PHT) is a first-line drug in the treatment of status epilepticus. However, the parenteral PHT formulation is associated with administration difficulties and therefore fosphenytoin (FosPHT), a PHT pro-drug, has been developed. As the peripheral (blood) and central (cerebrospinal fluid [CSF] and brain extracellular fluid [ECF]) kinetic inter-relationship of PHT after i.v. FosPHT administration is unknown we sought to ascertain the relationship and to compare it to that of i.v. PHT. A freely behaving rat model, which allows for the concurrent and temporal sampling of blood (jugular vein), CSF (cisterna magna) and brain ECF (frontal cortex and hippocampus), was used. PHT and FosPHT were administered by i.v. infusion and blood, CSF and microdialysate samples collected at timed intervals up to 6 hours. The pharmacokinetic parameters in plasma of PHT after PHT and FosPHT (30 and 60 mg/kg) administration were indistinguishable. The PHT plasma free fraction (free/total concentration ratio) was 0.25–0.31 and 0.26–0.31 for PHT and FosPHT, respectively. Mean PHT T max values for CSF were 9–13 minutes. The equivalent values in the frontal cortex and hippocampal ECF were 29–34 minutes. C max values increased dose-dependently and were independent of whether PHT or FosPHT was administered. Furthermore the kinetic profiles of PHT for the frontal cortex and hippocampus were indistinguishable suggesting that PHT distribution in the brain is not brain region specific. Thus, overall, the central and peripheral kinetics of PHT are indistinguishable after PHT and FosPHT.

Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit.

The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration may not be feasible.

Intravenous infusion of fosphenytoin produces prolonged pain relief: A case report

The objective of this case report is to emphasize the analgesic effect of antiepileptic drugs in those with neuropathic pain, confirm that fosphenytoin possesses these analgesic properties, and to highlight that intravenous administration of fosphenytoin for 24 hours can produce good quality pain relief that lasts for many weeks. A 37-year-old woman with a neuroma (caused by surgical intervention for an endometrial sarcoma) producing neuropathic pain unresponsive to opiates was successfully treated with intravenous infusion of 1,500 phenytoin equivalent units fosphenytoin for 24 hours. The pain relief after this and subsequent infusions persisted for between 3 and 14 weeks and was associated with a reduced opiate requirement and an increase in activities of daily living. Fosphenytoin infusion can give good quality pain relief in the patient with neuropathic pain. © 2002 by the American Pain Society

Inappropriate fosphenytoin use in the ED

The objective of the study was to evaluate how often intravenous (IV) fosphenytoin is used when oral phenytoin loading is possible. The methods included a retrospective chart review of all patients receiving IV fosphenytoin in the emergency department. We prospectively derived criteria that identify patients with seizures who could receive oral phosphenytoin loading (awake on arrival, alert, no emesis, and lack of endotracheal intubation, repeated seizures, or status epilepticus after arrival). The setting of the study was at an urban, university hospital emergency department with an annual census of 55,000 patients. The outcomes included the number of patients receiving IV fosphenytoin who could have received oral phenytoin loading. From February 1997 to June 1999, 55 patients received IV fosphenytoin. Thirty of these patients (55%, 95% confidence interval 41%-68%) were felt to have received fosphenytoin appropriately. The remaining 25 (45%, 95% confidence interval 32%-59%) patients could have been loaded orally with phenytoin. In a single institution, fosphenytoin administration is inappropriate almost half the time. Oral phenytoin loading is less expensive and safe.

Glucuronidation of Prodrug Reactive Site: Isolation and Characterization of Oxymethylglucuronide Metabolite of Fosphenytoin

This investigation was undertaken to identify the structure of a novel immunoreactive metabolite derived from fosphenytoin that has been hypothesized previously as present in sera from renally impaired patients receiving this prodrug. The metabolite was isolated from uremic sera using solid-phase extraction and HPLC. Structural analysis was performed using HPLC-tandem mass spectrometry, nuclear magnetic resonance (NMR), deuterium exchange, and chemical derivatization. Immunoreactivity was evaluated using a fluorescence polarization immunoassay. The metabolite had a parent ion at m/z 457 in the negative-ion mode and fragmented to yield the m/z 251 of phenytoin, as well as other mass fragments of phenytoin. Mass fragments associated with glucuronic acid were also present. The chromatographic peak corresponding to this metabolite demonstrated immunoreactivity sufficient to lead to falsely increased reported values for phenytoin immunoassays. The observed immunoreactivity was also proportional to the relative concentration of the metabolite in collected fractions. Analysis by NMR indicated the presence of phenyl groups with chemical shifts identical to those of phenytoin, as well as the presence of a methylene bridge, which was consistent with the same methylene bridge present on the phosphate ester of fosphenytoin. Comparative analysis of serum samples from renally impaired patients receiving phenytoin vs fosphenytoin using multiple reaction monitoring quantification demonstrated that this metabolite was associated with fosphenytoin administration. A unique immunoreactive oxymethylglucuronide metabolite derived from fosphenytoin has been isolated from sera from uremic patients receiving this prodrug.

Comparison of plasma levels and pharmacodynamics after intraosseous and intravenous administration of fosphenytoin and phenytoin in piglets.

OBJECTIVE: To compare plasma drug levels and pharmacodynamics of fosphenytoin or phenytoin when given intraosseously or intravenously in doses relevant to children. DESIGN: Prospective controlled randomized study. SETTING: University hospital animal laboratory. SUBJECTS: A total of 40 mixed-breed piglets (age, 4-6 months; weight, 20-40 kg). INTERVENTIONS: The animals were anesthetized, after which they underwent intubation, instrumentation, and mechanical ventilation. A central venous catheter and an arterial catheter were placed for monitoring and blood sampling. A peripheral intravenous catheter with a 15-gauge intraosseous needle was inserted for drug infusion. A total of 40 animals (ten per group) were randomly assigned to receive intravenous or intraosseous phenytoin or fosphenytoin infusions. Phenytoin (20 mg/kg) was infused over 20 mins, and fosphenytoin (20 mg phenytoin equivalent kg) was infused over 7 mins. All infusions were followed by the administration of a 5-mL normal saline flush. MEASUREMENTS AND MAIN RESULTS: Blood samples (3 mL) were drawn for use in determining drug levels before infusions (baseline) and 0, 5, 10, 15, 20, 30, 40, 50, 60, and 75 mins after the infusion had been completed. Repeated measures of analysis of variance were used to evaluate statistical significance (p <.05). Phenytoin levels were undetected at baseline. Free (10 to 20 &mgr;g/mL) and total (80 to 110 &mgr;g/mL) phenytoin levels were well above the therapeutic range (free, 1 to 2 &mgr;g/mL; total, 10 to 20 &mgr;g/mL) after infusion in the animals that received fosphenytoin. Significant differences in values were seen in free phenytoin levels at 0 to 10 mins (p <.05) and in total phenytoin levels at 0 to 20 mins (p <.05) between intraosseous phenytoin or fosphenytoin administration. Similar differences were also seen when piglets that received intravenous phenytoin were compared with those that received intravenous fosphenytoin. From 20 to 75 mins, all groups had free and total levels within the therapeutic range. There were no significant differences among heart rate and blood pressure in the groups. CONCLUSION: There is no need to adjust standard drug doses of phenytoin when given intraosseously. The initial high levels of phenytoin in the fosphenytoin groups are of concern because neurologic toxic effects may occur in humans at those levels. Slower infusion rates of fosphenytoin may be needed to avoid toxic levels.