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

Open AccessPublished:July 22, 2022DOI:https://doi.org/10.1016/j.braindev.2022.06.012

      Abstract

      Introduction

      We aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (CPHT).

      Methods

      We retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two CPHT measurements were analyzed, one 2–4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate CPHT.

      Results

      The present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2–27.2) mg/kg. The CPHT was 13.4 (8.6–18.9) μg/mL 2–4 h after the loading dose. The CPHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7–14.2) and 5.8 (3.7–10.0) μg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the CPHT on day 8 was estimated to be 5.74 (2.6–15.4) μg/mL at 5 mg/kg and 13.9 (5.7–31.0) μg/mL at 7.5 mg/kg.

      Conclusions

      In pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5–7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring CPHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.

      Keywords

      1. Introduction

      Fosphenytoin, which is rapidly converted to phenytoin by serum phosphatases, is a water-soluble prodrug of phenytoin. Phenytoin injections are insoluble in water, have a high pH, and cause local tissue irritation; therefore, fosphenytoin has been used in clinical practice to avoid these issues. Phenytoin also inhibits voltage-dependent sodium channels in neurons, showing anticonvulsant actions by inhibiting hyperexcitability. Fosphenytoin performed as well as levetiracetam and sodium valproate in a randomized controlled trial of patients with status epilepticus resistant to benzodiazepines [
      • Kapur J.
      • Elm J.
      • Chamberlain J.M.
      • Barsan W.
      • Cloyd J.
      • Lowenstein D.
      • et al.
      Randomized trial of three anticonvulsant medications for status epilepticus.
      ], and fosphenytoin is the second-line drug for status epilepticus [
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • Alldredge B.
      • Arya R.
      • Bainbridge J.
      • et al.
      Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: Report of the Guideline Committee of the American Epilepsy Society.
      ]. Fosphenytoin is advantageous compared with benzodiazepines because it has little effect on the patients’ level of consciousness. Therefore, fosphenytoin may be continued when assessing the patients’ level of consciousness, while preventing seizure recurrence. In Japan, for patients with status epilepticus, the dose of fosphenytoin for pediatric patients over 2 years of age is defined as follows: 22.5 mg/kg loading dose and 5–7.5 mg/kg/day maintenance dose. Therapeutic drug monitoring (TDM) is recommended to ensure the efficacy and safety of fosphenytoin, and the therapeutic range of total serum phenytoin concentration (CPHT) is 10–20 μg/mL [
      • Kutt H.
      • McDowell F.
      Management of epilepsy with diphenylhydantoin sodium. Dosage regulation for problem patients.
      ]. However, Takeoka et al. reported that a maintenance dose of 7.5–12 mg/kg/day fosphenytoin was less effective in maintaining the therapeutic range in infants [
      • Takeoka M.
      • Krishnamoorthy K.S.
      • Soman T.B.
      • Caviness V.S.
      Fosphenytoin in infants.
      ], and Moffett et al. recommended a maintenance dose of 6 mg/kg/dose fosphenytoin every 8 h for critically ill pediatric patients [
      • Moffett B.S.
      • Weingarten M.M.
      • Schmees L.R.
      • Galati M.
      • Erklauer J.
      • Riviello J.J.
      Fosphenytoin population pharmacokinetics in the acutely ill pediatric population.
      ]. Therefore, in Japan, the standard dosing regimen of fosphenytoin may not be able to maintain the therapeutic range, and a maintenance dose should instead be guided by TDM.
      There are some clinical issues associated with adjusting the dose of fosphenytoin. Phenytoin is a nonlinear pharmacokinetic drug following the Michaelis-Menten equation [
      • Yukawa E.
      • Higuchi S.
      • Aoyama T.
      Population pharmacokinetics of phenytoin from routine clinical data in Japan: an update.
      ], and it is more difficult to adjust the dose of fosphenytoin than that of drugs with linear pharmacokinetics. Nevertheless, the dose of fosphenytoin must be adjusted with as few blood samples as possible in clinical practice. Therefore, it is necessary to establish a dosing regimen that includes an appropriate time to measure CPHT. In this study, we evaluated the fosphenytoin dosing regimen, including identifying the optimal timing for the measurement of CPHT.

      2. Methods

      2.1 Patients

      The present study was conducted at Tokyo Women's Medical University, Yachiyo Medical Center. We retrospectively investigated pediatric patients who were treated with fosphenytoin for status epilepticus or seizure clusters between April 2013 and March 2018 and had two measurements of CPHT, one 2–4 h after the loading dose and another before the second dose. In addition, the patients had to be at least 2 years old as fosphenytoin is clinically indicated in Japan for patients aged 2 years or older. Considering the influence of serum albumin (Alb) on CPHT, patients with Alb levels < 3.5 g/mL were excluded.

      2.2 Data collection

      Data on age, weight, sex, target disease, initial and maintenance doses of fosphenytoin, concomitant use of antiepileptic drugs during fosphenytoin treatment, CPHT, and Alb were retrospectively collected from the electronic medical records of the patients.

      2.3 CPHT measurement method

      CPHT was analyzed using the chemiluminescence immunoassay with an ARCHITECT® analyzer i2000 SR (Abbott Japan Co., Ltd., Tokyo, Japan) in the hospital clinical laboratory.

      2.4 Estimating of individual pharmacokinetic parameters and simulation

      Individual pharmacokinetic parameters were estimated using the Bayesian method from CPHT measurements with BMs-Pod ver 8.03 (https://bmspod.web.fc2.com/), which is freely available software based on Microsoft Excel (Microsoft, Redmond, WA). This software incorporates the population pharmacokinetic model reported by Odani et al. [
      • Odani A.
      • Hashimoto Y.
      • Takayanagi K.
      • Otsuki Y.
      • Koue T.
      • Takano M.
      • et al.
      Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model.
      ] and is a one-compartment model based on Michaelis-Menten kinetics. This pharmacokinetic model incorporates body weight as a covariate for maximum elimination rate. Thus, metabolic capacity varies with body weight in this model. We simulated CPHT at 12 and 24 h after the loading dose from individual estimated parameters. In addition, we simulated and compared CPHT when administered the standard fosphenytoin dosing regimen in Japan (22.5 mg/kg as the loading dose, and a maintenance dose of 7.5 mg/kg every 24 h from 24 h after the loading dose) and when administered two increased maintenance dose regimens. In one of the regimens, the increased maintenance dose is 22.5 mg/kg for the initial dose and a maintenance dose of 7.5 mg/kg every 12 h from 12 h after the first administration. The other regimen is the same loading dose and a maintenance dose of 5 mg/kg every 12 h.

      2.5 Ethical approval

      The present study was approved by the Ethics Committee of Tokyo Women's Medical University (approval number: 5102). Patients were allowed to opt out of this study at any time, and this information was available on the hospital website.

      3. Results

      3.1 Patient characteristics

      Thirteen patients were initially selected, one patient was excluded because of Alb level < 3.5 g/mL, and 12 patients were included in this study. A summary of patient data is shown in Table 1.
      Table 1Summary of patient data (n = 12).
      PatientAge (year)Weight (kg)Alb (mg/dL)Loading dose of FOS (mg/kg)Concomitant antiepileptic drugsSeizure causeSeizure conditionsConvulsions after FOS loading doseLast convulsion dateDuration of FOS treatment (day)
      11019.84.622.7TPM, LEVEpilepsySCoccurredday 33
      2520.24.427.2PB, KBrEpilepsySCoccurredday 24
      3211.54.221.7MDZ, LEV, VPA, CHLEpilepsySCoccurredday 15
      41243.74.917.2LEV, VPAEpilepsySCnoneday 12
      5421.24.321.2DZPAfebrile convulsionSEnoneday 11
      6417.84.423.2MDZAESEoccurredday 26
      7416.24.223.1LEV, VPA, LTGEpilepsySCoccurredday 34
      8515.63.921.6MDZ, LEV, CBZ, CHL, THPAESEoccurredday 815
      949.353.620.9MDZFebrile convulsionSEnoneday 14
      104153.622.5MDZ, VPAAESEoccurredcontinue5
      11210.73.821.0MDZAESCnoneday 15
      121241.94.823.3MDZ, VPA, TPMEpilepsySEoccurredday 13
      Alb: serum albumin, FOS: fosphenytoin, AE: acute encephalopathy, SE: status epilepticus, SC: seizure clusters, TPM: topiramate, LEV: levetiracetam, PB: phenobarbital, KBr: potassium bromide, MDZ: midazolam, VPA: sodium valproate, CHL: chloral hydrate, DZP: diazepam, LTG: lamotrigine, CBZ: carbamazepine, THP: thiopental sodium.
      The median (range) age and weight of patients at the initial administration of fosphenytoin was 4 (2–12) years and 17.0 (9.4–43.7) kg, respectively. Regarding the seizure conditions, 6 patients had status epilepticus and 6 patients had seizure clusters. The diseases that caused the seizures were acute encephalopathy in 4 patients, pre-existing epilepsy in 6 patients, febrile convulsion in 1 patient, and afebrile convulsion in 1 patient. The median (range) loading dose was 22.1 (17.2–27.2) mg/kg, and the CPHT at 2–4 h after the loading dose of 13.4 (8.6–18.9) μg/mL; the CPHT of one patient was subtherapeutic level (Fig. 1). Among the patients with status epilepticus, 2 patients did not have convulsions after the loading dose and 2 patients showed seizure resolution within 1–3 days without recurrence of status epilepticus or seizure clusters. In the other two patients, one had recurrent status epilepticus and the other had convulsions at least once a day during fosphenytoin maintenance. Among the patients with seizure clusters, 2 patients did not have convulsions after the loading dose and 4 patients showed seizure resolution within 1–3 days without recurrence of status epilepticus or seizure clusters (Table 1). The median (range) duration of fosphenytoin treatment was 4 (1–15) days. The number of patients who received concomitant antiepileptic drugs that could affect the pharmacokinetics of fosphenytoin was seven; of these, 5 patients received sodium valproate, 1 received carbamazepine, and 1 received phenobarbital. Adverse effects requiring treatment were not observed during fosphenytoin administration.
      Figure thumbnail gr1
      Fig. 1Total serum phenytoin concentration after the initial loading dose (n = 12). The patients who did not receive concomitant medications affecting fosphenytoin pharmacokinetics are indicated with a white circle, patients who received sodium valproate are indicated with a white square, and patients who received cytochrome P450 enzyme inducers, phenobarbital and carbamazepine, are indicated with a white triangle.
      The pharmacokinetic parameters estimated from individual CPHT values are shown in Table 2. The median (range) maximum elimination rate (Vmax) was calculated to be 272.6 (197.9–431.3) mg/day. The Vmax per body weight decreased with body weight.
      Table 2Estimated pharmacokinetic parameters (n = 12).
      ParameterValue
      Vmax (mg/day)272.6 (197.9–431.3)
      Vmax (mg/day/kg)15.8 (9.9–21.2)
      km (μg /mL)9.1 (7.7–10.4)
      Vd (L/kg)1.1 (0.8–1.4)
      Data are presented as median (range).
      Vmax: maximum elimination rate, km: Michaelis-Menten constant, Vd: volume of distribution

      3.2 Simulation of CPHT

      The median (range) estimated CPHT at 12 and 24 h after the loading dose, calculated from individual pharmacokinetic parameters, was 9.5 (6.7–14.2) and 5.8 (3.7–10.0) μg/mL, respectively (Fig. 2). The ratio of CPHT expected to be within 10–20 μg/mL was 41.7% at 12 h after the loading dose and 0% at 24 h after the loading dose.
      Figure thumbnail gr2
      Fig. 2Estimated total serum phenytoin concentration at 12 and 24 h after the initial loading dose, calculated from individual pharmacokinetic parameters. Black circles are median values; white circles are individual values for patients who did not receive concomitant medications affecting fosphenytoin pharmacokinetics; white squares are individual values of patients who received sodium valproate; white triangles are individual values of those who received cytochrome P450 enzyme inducers (carbamazepine or phenobarbital).
      We estimated the CPHT for the standard dose regimen in Japan and for the two increased maintenance dose regimens (Fig. 3). The median (range) estimated CPHT for the standard dose regimen in Japan was 3.7 (1.1–8.6) μg/mL on day 4 and 2.52 (0.9–7.8) μg/mL on day 8. The median (range) estimated CPHT for the increased maintenance dose regimen of 5 mg/kg every 12 h was 7.1 (3.2–13.7) μg/mL on day 4 and 5.7 (2.6–15.4) μg/mL on day 8. The ratio of CPHT expected to be within 10–20 μg/mL was 16.7% on days 4 and 8. Furthermore, for the increased maintenance dose regimen of 7.5 mg/kg every 12 h, the median (range) estimated CPHT was 12.2 (6.1–20.6) μg/mL on day 4 and 13.9 (5.7–31.0) μg/mL on day 8. The ratio of CPHT expected to be within 10–20 μg/mL was 58.3% on day 4 and 50.0% on day 8.
      Figure thumbnail gr3
      Fig. 3Estimated total serum phenytoin concentration on day 4 and day 8 for the standard dosage regimen in Japan and for the two increased maintenance dose regimens. The standard regimen in Japan is 22.5 mg/kg as the initial dose, and a maintenance dose of 7.5 mg/kg every 24 h from 24 h after the first administration. In one of the increased maintenance dose regimens, the maintenance dose is 22.5 mg/kg for the initial dose and 7.5 mg/kg every 12 h from 12 h after the first administration. In the other, the same loading dose and a maintenance dose of 5 mg/kg every 12 h were used. Black circles are median values; white circles are individual values for patients who did not receive concomitant medications affecting fosphenytoin pharmacokinetics; white squares are individual values of the patients who received sodium valproate; white triangles are individual values of those who received cytochrome P450 enzyme inducers (carbamazepine or phenobarbital).

      3.3 Measured CPHT during a maintenance dose of fosphenytoin

      Eleven of the 12 patients were treated with a maintenance dose of fosphenytoin; 1 patient received just one additional dose, 1 patient received the regular 7.4 mg/kg every 24 h, and 9 patients received 5.9–9.3 mg/kg every 12 h. CPHT of 10 patients was measured during the maintenance dosing (Table 3). Two patients had Alb levels < 3.5 g/mL, and for the remaining eight patients, the median (range) trough level of CPHT was 11.4 (3.0–19.4) μg/mL and the range of maintenance doses was 5.9–9.3 mg/kg/dose. Among the eight patients, the maintenance dosing interval was 24 h for one patient and 12 h for seven patients. Patient 8 was treated with fosphenytoin 7.2 mg/kg every 12 h, but status epilepticus recurred; CPHT was then measured on day 8, and the observed value was 3.0 µg/mL.
      Table 3Maintenance doses of fosphenytoin and total serum phenytoin concentrations.
      PatientDose (mg/kg)Dosing interval (h)CPHT (μg/mL)Alb (mg/dL)Date of measurement
      17.61219.34.6day 4
      27.42411.94.5day 5
      37.01210.24.3day 5
      65.9129.33.5day 5
      79.31219.43.9day 4
      87.2123.04.1day 8
      117.01210.83.8day 4
      126.41215.54.8day 4
      417.224
      5
      96.412(7.8) a3.1day 4
      107.512(7.5) a3.4day 5
      CPHT: total serum phenytoin concentration, Alb: serum albumin.
      a: Reference value with Alb level < 3.5 g/mL

      4. Discussion

      The results of the present study suggest that a loading dose of 22.5 mg/kg fosphenytoin is appropriate, and if fosphenytoin administration is to be continued, we recommend that a maintenance dose should be started 12 h after the loading dose. In Japan, the maintenance dose of fosphenytoin is 5–7.5 mg/kg every 24 h, but 7.5 mg/kg every 24 h is not likely to maintain the therapeutic range. According to our results, a maintenance dose of 5–7.5 mg/kg every 12 h could maintain the therapeutic range.
      There is no clear evidence for the prevention of recurrence after the convergence of status epilepticus. However, in clinical practice, antiepileptic drugs are continued to prevent recurrence until the causative disease is determined. Fosphenytoin and levetiracetam are specifically selected for use during the evaluation of a patient’s level of consciousness. The therapeutic range for fosphenytoin is generally 10–20 μg/mL [
      • Kutt H.
      • McDowell F.
      Management of epilepsy with diphenylhydantoin sodium. Dosage regulation for problem patients.
      ], and a dosing regimen and TDM that can maintain this range are important. In patients who do not achieve seizure control within the therapeutic range or who have difficulty controlling CPHT even with appropriate dosing regimens, other antiepileptic drugs should be considered. However, Borofsky et al. reported that CPHT in pediatric patients with controlled epilepsy was above 5 μg/mL, and therefore, CPHT of up to 5 μg/mL may be acceptable if seizures are controlled [
      • Borofsky L.G.
      • Louis S.
      • Kutt H.
      • Roginsky M.
      Diphenylhydantoin: Efficacy, toxicity, and dose-serum level relationships in children.
      ]. CPHT less than 5 μg/mL is not recommended, and in fact, one patient with recurrent status epilepticus had a CPHT of 3.0 μg/mL. The patient was diagnosed with acute encephalopathy and continued to be treated with fosphenytoin for seizure prophylaxis but developed a late seizure. Further studies are needed to investigate the relationship between the efficacy of fosphenytoin in preventing recurrence and the therapeutic range of CPHT.
      Tanaka et al. performed population pharmacokinetic analysis of fosphenytoin and suggested that the loading dose of fosphenytoin in children should be 22.5 mg/kg [
      • Tanaka J.
      • Kasai H.
      • Shimizu K.
      • Shimasaki S.
      • Kumagai Y.
      Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers.
      ]. In this study, the median CPHT for 2–4 h was 13.4 μg/mL with a median loading dose of 22.1 mg/kg, and therefore, 22.5 mg/kg fosphenytoin is considered a safe and optimal loading dose. However, a phenytoin loading dose of 20 mg/kg is recommended for status epilepticus [
      • Prasad M.
      • Shenton P.
      • Dietz S.
      • Saroha V.
      • Whitehouse W.P.
      What is the easier and more reliable dose calculation for iv phenytoin in children at risk of developing convulsive status epilepticus, 18 mg/kg or 20 mg/kg?.
      ,
      • Piper J.D.
      • Hawcutt D.B.
      • Verghese G.K.
      • Spinty S.
      • Newland P.
      • Appleton R.
      Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading.
      ], which translates to 30 mg/kg fosphenytoin, as the ratio of fosphenytoin to phenytoin is 1.5. Thus, the loading dose of fosphenytoin could be increased from 22.5 mg/kg.
      In children, the maximum elimination rate of phenytoin is higher than that in adults [
      • Blain P.G.
      • Mucklow J.C.
      • Bacon C.J.
      • Rawlins M.D.
      Pharmacokinetics of phenytoin in children.
      ], and the time to reach below 10 μg/mL after the loading dose of fosphenytoin was also faster than that in adults [
      • Tanaka J.
      • Kasai H.
      • Shimizu K.
      • Shimasaki S.
      • Kumagai Y.
      Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers.
      ]. In this study, the median CPHT estimated from individual pharmacokinetic parameters was 9.5 μg/mL after 12 h and 5.8 μg/mL after 24 h from the loading dose. Therefore, the maintenance dose of fosphenytoin should be started 12 h after the loading dose. In a simulation of phenytoin using a physiologically based pharmacokinetic model, a loading dose of 18 mg/kg and a maintenance dose of 5 mg/kg every 12 h were the highest rates for maintaining a peak CPHT of 10–20 μg/mL [
      • Batchelor H.
      • Appleton R.
      • Hawcutt D.B.
      Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software.
      ]. The results can be extrapolated to fosphenytoin with a loading dose of 27 mg/kg and a maintenance dose of 7.5 mg/kg. In our simulation with the estimate from individual pharmacokinetic parameters, a loading dose of 22.5 mg/kg and a maintenance dose of 7.5 mg/kg every 24 h starting at 24 h after the loading dose would not be able to maintain a trough CPHT of 10–20 μg/mL, and 83.3% of the patients had CPHT below 5 μg/mL. Whereas, with a loading dose of 22.5 mg/kg, followed by a maintenance dose of 7.5 mg/kg every 12 h starting at 12 h after the loading dose, the median trough CPHT was expected to be 12.2 μg/mL on day 4 and 13.9 μg/mL on day 8. However, CPHT increased over time in two patients, and it was estimated to be over 20 μg/mL on day 8. The population pharmacokinetic model used in this study, proposed by Odani et al. [
      • Odani A.
      • Hashimoto Y.
      • Takayanagi K.
      • Otsuki Y.
      • Koue T.
      • Takano M.
      • et al.
      Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model.
      ], incorporates body weight as a covariate of Vmax, and Vmax per body weight decreases with increasing body weight. Other population pharmacokinetic models incorporate body weight or fat-free mass as a covariate for metabolic clearance [
      • Moffett B.S.
      • Weingarten M.M.
      • Schmees L.R.
      • Galati M.
      • Erklauer J.
      • Riviello J.J.
      Fosphenytoin population pharmacokinetics in the acutely ill pediatric population.
      ,
      • Tanaka J.
      • Kasai H.
      • Shimizu K.
      • Shimasaki S.
      • Kumagai Y.
      Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers.
      ]. Therefore, for the same dose (mg/kg), the CPHT will be higher in patients with a higher body weight, because the elimination rate of phenytoin per body weight is lower in patients with a higher body weight. Both patients with an estimated supratherapeutic level were 12 years old, the oldest of the patients in this study, and over 40 kg. For heavier children, a regimen with a maintenance dose of 5 mg/kg every 12 h may be appropriate; when simulated with the population pharmacokinetic model of Odani et al. [
      • Odani A.
      • Hashimoto Y.
      • Takayanagi K.
      • Otsuki Y.
      • Koue T.
      • Takano M.
      • et al.
      Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model.
      ], 30 kg was the borderline weight for determining a maintenance dose of 7.5 or 5 mg/kg (data not shown). In contrast, Moffett et al. recommended that the optimum dosing regimen of fosphenytoin was a loading dose of 20 mg/kg and a maintenance dose of 6 mg/kg every 8 h [
      • Moffett B.S.
      • Weingarten M.M.
      • Schmees L.R.
      • Galati M.
      • Erklauer J.
      • Riviello J.J.
      Fosphenytoin population pharmacokinetics in the acutely ill pediatric population.
      ], and this daily maintenance dose is higher than that determined in our study. Currently, the optimal maintenance dose is not clear, but the maintenance dose should be higher than 7.5 mg/kg every 24 h to maintain the therapeutic range, and a maintenance dose of 5–7.5 mg/kg every 12 h would help achieve this.
      The CPHT at 2 h after a loading dose of fosphenytoin is important in confirming that CPHT is within the therapeutic range [
      • Falco-Walter J.J.
      • Bleck T.
      Treatment of established status epilepticus.
      ] and is needed for determining the maintenance doses if treatment with fosphenytoin should be continued. Immunoassays should not be performed up to 2 h after administration because serum fosphenytoin and phenytoin interact with each other in immunoassays [
      • Kugler A.R.
      • Annesley T.M.
      • Nordblom G.D.
      • Koup J.R.
      • Olson S.C.
      Cross-reactivity of fosphenytoin in two human plasma phenytoin.
      ]. In clinical practice, the CPHT after 2–4 h of administration is considered the peak concentration with complete distribution. The concept of volume of distribution (Vd) is not different from that of other drugs; therefore, estimating the CPHT that increases with a single fosphenytoin dose is possible. The median Vd of fosphenytoin was 1.1 L/kg in this study. In pediatric patients, the Vd of fosphenytoin was not affected by obesity and was found to be 0.92 L/kg in obese patients and 0.97 L/kg in non-obese patients [
      • Prusakov A.B.
      • Patel A.D.
      • Cole J.W.
      Impact of obesity on fosphenytoin volume of distribution in pediatric patients.
      ], which was similar to our results. In contrast, it has been reported that the Vd of phenytoin was 1.6 L/kg at 1 year of age but decreased to 0.6 L/kg at 10 years of age [
      • Koren G.
      • Brand N.
      • Halkin H.
      • Dany S.
      • Shahar E.
      • Barzilay Z.
      Kinetics of intravenous phenytoin in children.
      ]. Therefore, the Vd of fosphenytoin may be affected by age, and CPHT measurement after 2 h of the loading dose was useful in determining the maintenance dose. Furthermore, Riviello et al. recommended that the CPHT should be checked after 2 h of phenytoin loading, and if the CPHT after 2 h is in the therapeutic range, the maintenance dose should be started after 12 h, and if the CPHT is at a subtherapeutic level, the maintenance dose should be started earlier than 12 h [
      • Riviello J.J.
      • Roe E.J.
      • Sapin J.I.
      • Grover W.D.
      Timing of maintenance phenytoin therapy after intravenous loading dose.
      ]. In addition to their recommendation, we consider that the CPHT should be measured before the maintenance dose. If CPHT is obtained after 2 h and before the second dose, the CPHT that increases with a single dose and the decrease in CPHT with time can be estimated. In particular, the ideal timing of measurement before the second dose and the interval between maintenance doses should be 12 h. For instance, if fosphenytoin was administered at 22.5 mg/kg and CPHT was 15 μg/mL at 2 h after the loading dose and 10 μg/mL at 12 h after the loading dose, the same CPHT level should be continued at 7.5 mg/kg every 12 h beginning 12 h after the loading dose. However, individual pharmacokinetics may be altered, for example, due to drug interactions or changes in systemic conditions. CPHT may also change, and this is commonly observed in clinical practice. Therefore, if continued treatment with fosphenytoin is needed after 3–4 days of fosphenytoin initiation, CPHT should be measured before administration. For the seven patients who received fosphenytoin of 5.9–9.3 mg/kg every 12 h continuously, one patient had CPHT of 3.0 μg/mL (subtherapeutic level) and two patients had CPHT of 19.3 and 19.4 μg/mL, close to the supratherapeutic levels. One patient treated with a maintenance dose of 7.4 mg/kg every 24 h had a CPHT of 11.9 μg/mL, in the therapeutic range. The cause of this variation has not been clarified, and further studies are needed.
      This study had some limitations. First, the number of patients was small. Second, free serum phenytoin concentration was not measured. Third, CPHT may have been affected by concomitant antiepileptic drugs. In this study, concomitant antiepileptic drugs that could decrease CPHT were sodium valproate, phenobarbital, and carbamazepine [
      • Patsalos P.N.
      • Perucca E.
      Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs.
      ]. In particular, the drug interaction between sodium valproate and phenytoin is that of plasma protein binding displacement, which decreases CPHT but does not change free phenytoin concentration [
      • Perucca E.
      • Hebdige S.
      • Frigo G.M.
      • Gatti G.
      • Lecchini S.
      • Crema A.
      Interaction between phenytoin and valproic acid: Plasma protein binding and metabolic effects.
      ,

      Tsanaclis LM, Allen J, Perucca E, Routledge PA, Richens A. Effect of valproate on free plasma phenytoin concentrations. Br J Clin Pharmacol 1984;18:17–20.

      ]. Tsanaclis et al. showed that the concomitant use of sodium valproate decreased the mean CPHT from 13.4 μg/mL to 10.2 μg/mL [

      Tsanaclis LM, Allen J, Perucca E, Routledge PA, Richens A. Effect of valproate on free plasma phenytoin concentrations. Br J Clin Pharmacol 1984;18:17–20.

      ]. Fourth, patients with hypoalbuminemia were not studied. In patients with hypoalbuminemia and/or concomitant use of drugs that cause plasma protein binding displacement, measurement of free phenytoin concentration is necessary, but it is not a routine practice. In such patients, it would be safe to control CPHT around 10 μg/mL while monitoring the toxicity and Alb level. Lastly, genetic polymorphisms were not assessed in this study. Genetic polymorphisms in CYP2C9 and CYP2C19 have been reported to affect interindividual variation [
      • Yamamoto Y.
      • Takahashi Y.
      • Imai K.
      • Miyakawa K.
      • Ikeda H.
      • Ueda Y.
      • et al.
      Individualized phenytoin therapy for Japanese pediatric patients with epilepsy based on CYP2C9 and CYP2C19 genotypes.
      ], and further research in this regard may result in more individualized dosing regimens.

      5. Conclusion

      In pediatric patients, a loading dose of fosphenytoin at 22.5 mg/kg is appropriate, and maintenance dosing should be started 12 h after the loading dose to maintain the CPHT in the therapeutic range. A maintenance dose of 5–7.5 mg/kg/dose every 12 h may be better than the current Japanese dosing regimen, and dosing should be adjusted according to TDM. We recommend that CPHT be measured at 2 h and 12 h after the loading dose to confirm not only the therapeutic range but also to simplify and safely adjust the dosage.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      None.

      Funding

      This study was partially supported by a Grant-in-Aid for Research on Measures for Intractable Diseases ( 21FC1005 ) from the Ministry of Health, Labor and Welfare, Japan , to J.T.

      Authorship statement

      All authors met the ICMJE authorship criteria. GO and EK contributed to the conceptualization and design of the study. GO contributed to data collection. GO, EF, and KT performed data analysis. GO, KY, and JT interpreted the results. GO and EK contributed to drafting and editing the manuscript. EF, KT, KY, and JT provided suggestions on the study and revised the manuscript. All authors have read and approved the final manuscript.

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