What is the recommended dose regimen of fosphenytoin in obese patients?

What is the recommended dose regimen of fosphenytoin in obese patients?

Comment by InpharmD Researcher

Per 2016 American Epilepsy Society guidelines, a single dose of fosphenytoin 20 mg phenytoin sodium equivalent (PE)/kg to a maximum dose of 1,500 mg PE/dose is recommended as a second-line therapy if benzodiazepine fails to provide adequate seizure control. However, this dosing strategy has a level rating of U, unproven treatment, due to lack of data. Available data evaluating the influence of obesity on fosphenytoin dosing are limited to retrospective analyses in which some suggest that a dose capping should be done cautiously since arbitrary total dose limitations in obese patients may yield significantly lower post-load concentrations.

Pubmed: fosphenytoin obese = 4 results

Background

The 2016 American Epilepsy Society guidelines for the treatment of status epilepticus recommend a single dose of fosphenytoin 20 mg phenytoin sodium equivalent (PE)/kg to a maximum dose of 1500 mg PE/dose as second-line therapy if a benzodiazepine does not achieve seizure control. This dosing strategy has a level rating of U, unproven treatment, due to inadequate or insufficient data. Fosphenytoin is primarily recommended over phenytoin based on improved tolerability. [1]

A research forum abstract discussed a retrospective cohort (N= 58) of obese patients (body mass index 32.8 kg/m2) with status epilepticus receiving a fosphenytoin loading dose of 20 mg/kg without a capped dose. Based on the primary endpoint of total phenytoin plasma concentrations within therapeutic range after a loading dose (15 to 30 mcg/mL), 60.3% (35/58 patients) achieved targeted plasma concentrations. The secondary endpoint of percent free phenytoin plasma concentrations with therapeutic range after a loading dose (1.5 to 3 mcg/mL) was achieved in 75.8% of patients. On average, patients had received a total loading dose of 1,738 mg with albumin 3.3 g/dL. Adverse events were not noted for any patients. Based on these results, the authors suggest the uncapped fosphenytoin loading dose is safe and effective for obese patients with status epilepticus. [2]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the recommended dose regimen of fosphenytoin in obese patients?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-5 for your response.

Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex
Design	Retrospective, single-center, cohort study N= 195
Objective	Primary: to evaluate the effects of obesity and sex on serum phenytoin concentrations achieved following phenytoin or fosphenytoin loading doses (LDs) versus a nonobese cohort Secondary: to compare the calculated obesity phenytoin LD equation with actual doses administered
Study Groups	Non-obese (n= 141) Obese (n= 54)
Inclusion Criteria	Aged ≥18 years; received IV phenytoin ≥10 mg/kg or fosphenytoin ≥10 mg phenytoin equivalents (PE)/kg; had a free phenytoin concentration drawn between one and six hours after the end of the infusion; had a free phenytoin serum concentration obtained following the LD
Exclusion Criteria	Pediatric and pregnant patients
Methods	The institution did not have standardized recommendations for dose capping as well as for when to obtain free phenytoin levels after a LD. Patients with exposure to phenytoin or fosphenytoin prior to their IV LD were required to have baseline phenytoin concentrations that were undetectable. For each obese patient, the phenytoin LD was determined using an equation based on total body weight (TBW) and ideal body weight (IBW) [LD = 14 mg/kg (IBW) + 19 mg/kg (TBW − IBW)] . The calculated doses were then compared with the actual doses administered, and the corresponding phenytoin concentrations were examined.
Duration	June 1, 2014, through October 31, 2017
Outcome Measures	Dose range and phenytoin levels difference; dose range and phenytoin levels difference by sex; time level obtained postdose
Baseline Characteristics		Non-obese (n= 141)	Obese (n= 54)	p-value
	Age (range), years	60.9 (41.1 to 72)	57.4 (45.4 to 68.7)	0.52
	Sex Male Female	83 (58.9%) 58 (41.1%)	27 (50%) 27 (50%)	0.26 - -
	Body mass index (range), kg/m²	23.2 (21.2 to 25.8)	35.9 (32.5 to 39.9)	<0.001
	Weight, kg TBW IBW	68.0 (58.1 to 79.1) 63.8 (55.9 to 73.0)	104.2 (85.4 to 130.0) 63.8 (54.1 to 73.1)	<0.001 0.98
	Drug Phenytoin Fosphenytoin	41 (29.1%) 100 (70.9%)	17 (31.5%) 37 (68.5%)	0.74 - -
	The median dose of phenytoin or fosphenytoin in obese patients in our study was 1,700 mg, ranging from 950 to 2,520 mg with a resultant median free phenytoin level of 1.7 μg/mL. All but 6 patients (11.1%) received a dose of greater than 1,500 mg.
Results	Endpoint	Non-obese (n= 141)	Obese (n= 54)	p-value
	Dose (range), mg Dose (range) mg/kg TBW	1,270 (1,000 to 1,490) 20.0 (18.6 to 20.0)	1,700 (1,517 to 2,000) 17.0 (14.9-20.0)	<0.001 <0.001
	Free level (μg/mL)	1.8 (1.5 to 2.1)	1.7 (1.4 to 2.0)	0.16
	Free level distribution, n (%) <1 μg/mL 1-2 μg/mL >2 μg/mL	8 (5.7%) 92 (65.2%) 41 (29.1%)	3 (5.6%) 38 (70.1%) 13 (24.1%)	0.78 - - -
	Time level obtained postdose, hours	3.4 ± 1.4	3.1 ± 1.3	0.28
	Dosing and Phenytoin Levels by Sex
	Endpoint	Male	Female	p-value
	Non-obese Free level (μg/mL) Dose (mg) Dose (mg/kg) Weight (kg) BMI	(n= 83) 1.9 (1.5 to 2.2) 1320 (1030 to 1600) 20.0 (18.6 to 20.0) 70.3 (60 to 83.8) 23.2 (21.0 to 25.8)	(n= 58) 1.8 (1.5 to 2.0) 1200 (1000 to 1360) 20.0 (18.0 to 20.0) 61.5 (55.0 to 77.7) 23.3 (21.3 to 25.8)	- 0.16 0.012 0.93 <0.001 0.50
	Obese Free level, μg/mL Dose, mg Dose, mg/kg Weight, kg BMI, kg/m²	(n= 27) 1.6 (1.2 to 2.1) 2000 (1590 to 2070) 15.0 (14.0 to 19.2) 116.9 (102.1 to 132.5) 36.3 (33.2 to 39.9)	(n= 27) 1.7 (1.4 to 2.0) 1580 (1510 to 1900) 19.9 (15.0 to 20.0) 90.0 (78.2 to 106.6) 33.8 (31.2 to 40.0)	0.24 0.26 0.008 <0.001 0.32
	Maximum phenytoin LD of 1,500 mg will likely underdose some patients. Furthermore, the prevalence of free phenytoin concentrations that were less than 1 μg/mL in patients receiving doses of 10 mg/kg suggests that LDs should be at least 15 mg/kg.
Adverse Events	No difference in hypotension (mean arterial pressure (MAP) <70 mm Hg): Obese, 27% vs. non-obese, 18% (p= 0.356); nystagmus (two patients)
Study Author Conclusions	This study suggests that phenytoin or fosphenytoin LDs should be at least 15 mg/kg of actual body weight. Obese men may receive a dose of 15 mg/kg based on actual body weight, whereas women need a higher dose of 20 mg/kg. Use of weight-based dosing for obese patients obviates the need for the obese dosing equation. Dose capping should be done cautiously because weight-based dosing may warrant larger absolute phenytoin doses.
InpharmD Researcher Critique	This study was limited due to its retrospective nature and relatively small sample size in the obese cohort. Additionally, post-load serum phenytoin concentrations were drawn at varying times that may have affected the results. Since drug-drug interactions may have potentially altered the drug concentrations, precise peak concentrations can not be determined.

References:

DasGupta R, Alaniz C, Burghardt D. Evaluation of intravenous phenytoin and fosphenytoin loading doses: influence of obesity and sex. Ann Pharmacother. 2019;53(5):458-463. doi: 10.1177/1060028018818785

Impact of Obesity on Fosphenytoin Volume of Distribution in Pediatric Patients
Design	Retrospective, single-center review N= 37
Objective	To examine the differences in phenytoin V_D between pediatric patients with obese versus normal body habitus and evaluate the correlation of other factors with serum phenytoin levels
Study Groups	Non-obese (n= 25) Obese (n= 12)
Inclusion Criteria	Pediatric patients who received intravenous (IV) loading dose of fosphenytoin (≥ 10 mg of phenytoin equivalent per kg [mgPE/kg])
Exclusion Criteria	Received maintenance phenytoin therapy prior to the loading dose
Methods	Patients were identified by chart review.
Duration	January 1, 2013, to December 31, 2015
Outcome Measures	Serum phenytoin levels, volume of distribution (V_D)
Baseline Characteristics		Non-obese (n= 25)	Obese (n= 12)	p-value
	Age, years (range)	8.44 (2 to 17)	5.92 (2 to 14)	NS*
	Male	15 (60%)	11 (91.6%)	NS
	Weight (range)	31.26 (11.05 to 79)	32.65 (18.7 to 101.2)	NS
	BMI (range)	17.1 (9.9 to 28.2)	21.76 (18.2 to 31.6)	0.001
	*NS: not significant
Results	Endpoint (range)	Non-obese (n= 25)	Obese (n= 12)	p-value
	Total fosphenytoin dose, mgPE/kg	22.84 (9.97 to 50.63)	25.96 (10.34 to 35.13)	0.28
	Free phenytoin level, mcg/mL	2.9 (2 to 4.7)	3.75 (2.9 to 4.6)	0.3
	Total phenytoin level, mcg/mL	25.32 (11.4 to 36.1)	29.5 (19.9 to 43.3)	0.09
	Time fosphenytoin dose and phenytoin level, h	3.07 (0 to 20.88)	3.89 (0.28 to 16.38)	0.36
	Apparent V_D, L/kg	0.97 (0.36 to 2.61)	0.92 (0.25 to1.34)	0.76
Adverse Events	N/A
Study Author Conclusions	The V_D of fosphenytoin appears to be similar between obese and nonobese children, suggesting loading dose adjustments for obese children may not be necessary. Despite a variety of dosing strategies, all patients in this study achieved a therapeutic serum phenytoin level. Future research is needed to evaluate the clinical resolution of seizures with various fosphenytoin doses and to evaluate the utility of phenytoin serum drug monitoring in the setting of pediatric status epilepticus.
InpharmD Researcher Critique	This small cohort study was performed at a single institution with a small patient population. Due to being a retrospective chart review, this study was subject to the typical limitations and selection bias based on the study design.

References:

Prusakov AB, Patel AD, Cole JW. Impact of obesity on fosphenytoin volume of distribution in pediatric patients. J Child Neurol. 2018;33(8):534-536.

Assessment of Dose Capping in Phenytoin Loading Practices in the Emergency Department and the Impact of an Emergency Medicine Pharmacist
Design	Single-center, retrospective analysis N= 117
Objective	To compare the dosing of intravenous (IV) phenytoin or fosphenytoin and achievement of target concentrations in patients weighing 100 kg or more with those weighing less than 100 kg, as well as explore the contributions of Emergency medicine pharmacist (EPh) on the dosing of this agent
Study Groups	Patients weighing ≥100 kg (n= 42) Patients weighing <100 kg (n= 75)
Inclusion Criteria	Received at least one dose of IV phenytoin or fosphenytoin and admitted through the emergency department (ED)
Exclusion Criteria	Less than 18 years of age, pregnant, received phenytoin at an outside facility, or there was an inability to obtain a post-load concentration
Methods	Patients were retrospectively screened for inclusion from a pharmacy database of patients and subdivided into patients weighing ≥100 kg and <100 kg. To evaluate the impact of an EPh, IV phenytoin orders placed during the EPh's hours were compared with those placed outside of those hours. There existed no specific ED protocol regarding phenytoin loading doses or for specific dose capping.
Duration	From 2009 to 2011
Outcome Measures	Primary: achievement of target concentrations (e.g., 10-20 μg/mL) Secondary: achievement of target concentrations with the presence of an EPh
Baseline Characteristics		Patients weighing ≥100 kg (n= 42)	Patients weighing <100 kg (n= 75)	p-value
	EPh group	32 (76.2%)	44 (58.7%)	0.057
	Age, years	48.5 ± 14	51.8 ± 16.7	0.276
	Female	17 (40.5%)	53 (70.7%)	0.001
	Body mass index, kg/m²	38.7 ± 8.6	29.5 ± 4.1	0.001
	Indication Traumatic brain injury Subarachnoid hemorrhage Motor vehicle collision Subdural hematoma Seizure Other	2 (4.8%) 2 (4.8%) 0 (0) 1 (2.4%) 35 (83.3%) 4 (9.5%)	6 (8.0%) 5 (6.7%) 0 (0) 8 (10.7%) 61 (81.3%) 7 (9.3%)	0.506 0.677 1.000 0.107 0.787 0.973
	Home medications Amiodarone Carbamazepine Oxcarbamazepine Phenobarbital Valproic acid Phenytoin	0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (7.1%)	2 (2.7%) 2 (2.7%) 2 (2.7%) 3 (4.0%) 2 (2.7%) 9 (12.0%)	0.286 0.286 0.286 0.189 0.286 0.406
	Baseline albumin	3.6 ± 0.6	3.4 ± 0.6	0.282
	Baseline serum creatinine	1.1 ± 0.5	1.4 ± 2.7	0.431
	Baseline phenytoin serum concentration	2.2 ± 2.1	3.1 ± 3.9	0.727
Results	Endpoint	Patients weighing ≥100 kg (n= 42)	Patients weighing <100 kg (n= 75)	p-value
	Phenytoin load Fosphenytoin Phenytoin	25 (59.5%) 17 (40.5%)	56 (74.7%) 18 (24%)	0.089 0.062
	Phenytoin load, mg/kg	16.0 ± 2.9	18.6 ± 3.1	0.001
	Time from phenytoin administration to concentration drawn, minute	217.5 ± 64.0	212.7 ± 100.6	0.782
	Postload concentration within target range (10-20 μg/mL)	27 (64.3%)	50 (66.7%)	0.795
	Postload concentration within target range after albumin adjustment (10-20 μg/mL)	28 (66.7%)	46 (61.3%)	0.566
	Post-load concentration, μg/mL	15.1 ± 5.2	16.0 ± 5.1	0.374
	Albumin-adjusted post-load concentration, μg/mL	15.8 ± 5.3	17.2 ± 5.4	0.190
	Dose <15 mg/kg	12 (28.6%)	6 (8.0%)	0.003
	Those ≥100 kg who received less than 15 mg/kg were found to have significantly lower post-load concentrations than those that received 15 mg/kg or more regardless of the total dose (11.5 μg/mL vs. 16.5 μg/mL; p= 0.003). The presence of an EPh was found to result in significantly higher rates of post-load concentrations within the therapeutic range across all groups (72.4% vs. 53.7%; p= 0.04).
Adverse Events	No adverse effects attributed to phenytoin therapy were documented in either group.
Study Author Conclusions	The available data suggest that artificial total dose limitations in patients yield significantly lower post-load concentrations, potentially delaying seizure control in the acute setting. The presence of EPhs at the bedside increases the success of initial phenytoin dosing strategies in this population.
InpharmD Researcher Critique	The study is subject to the limitations inherent to a retrospective analysis (e.g., delays in administering phenytoin, delays in obtaining post-infusion laboratory values). Total phenytoin concentrations and correction for hypoalbuminemia were evaluated which have the potential to inaccurately represent the true serum concentration.

References:

Holder MC, Bailey AM, Baum RA, et al. Assessment of dose capping in phenytoin loading practices in the emergency department and the impact of an emergency medicine pharmacist. J Am Coll Clin Pharm. 2019:2(6):633-637. doi:10.1002/jac5.1086

IV Fosphenytoin in Obese Patients: Dosing Strategies, Safety, and Efficacy
Design	Single-center, retrospective chart review N= 410
Objective	To assess the safety and efficacy of fosphenytoin loading doses in patients with different body mass indices (BMIs)
Study Groups	Non-obese (n= 280) Obese (n= 130)
Inclusion Criteria	Age > 18 years, received a loading dose of IV fosphenytoin
Exclusion Criteria	Received fosphenytoin dose less than 10 mg/kg actual body weight, did not have serum phenytoin level obtained within 24 hours following loading dose, received intramuscular fosphenytoin, did not have complete medical records
Methods	Patients who fulfilled the criteria for inclusion were divided into obese (body mass index [BMI] > 30 mg/m²) and non-obese groups (BMI < 30 mg/m²). Serum phenytoin levels were collected between 1 to 24 hours after the loading dose.
Duration	Data collection period: January 1, 2008, to December 31, 2012
Outcome Measures	Patients within the therapeutic range for fosphenytoin total drug level (10 to 20 mcg/mL) or free drug level (1 to 2 mcg/mL), time from fosphenytoin administration to serum drug level, requiring second anti-epileptic drug or additional fosphenytoin load due to continued seizure activity
Baseline Characteristics		Non-obese (n= 280)	Obese (n= 130)	p-value
	Age, years	58 (18 to 93)	56 (18 to 89)	0.42
	Male	161 (58%)	73 (56%)	0.80
	Seizure history Cardiac history	86 (31%) 48 (17%)	33 (25%) 26 (20%)	0.27 0.48
	Fosphenytoin dose, mg/kg	18 (10 to 32)	17 (10 to 25)	0.09
Results	Endpoint	Non-obese (n= 280)	Obese (n= 130)	p-value
	Median total drug level	17.3 (13.7 to 20.9)	15.7 (12.8 to 18.9)	0.002
	Median free drug level	2 (1.7 to 2.5)	2.1 (1.7 to 2.5)	0.26
	Time from fosphenytoin administration to serum drug level	11 (6 to 16)	11 (7 to 15)	0.89
	Required second anti-epileptic drug Required additional fosphenytoin load for seizure control	23% 12%	31% 15%	0.07 -
	Adverse events Nystagmus Ataxia Hypotension Bradycardia Vasopressor use Held doses	31 (11.1%) 4 (1.4%) 104 (37.1%) 19 (6.8%) 65 (23.2%) 11 (3.9%)	6 (4.6%) 1 (0.8%) 56 (43.1%) 7 (5.4%) 33 (25.4%) 3 (2.3%)	0.03 1.00 0.25 0.59 0.63 0.56
Study Author Conclusions	The incidence of adverse events and the need for repeat loading antiepileptic medications were similar between the two groups. From our findings, the patients in our study did not receive empiric loading dose adjustments and the current method of loading fosphenytoin achieves similar outcomes, regardless of the patient's BMI.
InpharmD Researcher Critique	This was a single-center, retrospective study with results limited by its location and possible recruitment bias. For example, those with incomplete medical records were excluded from the study. Patients were stratified based on obesity rating rather than the dosage of treatment received. But from the results, a fosphenytoin dose at an average of 17 mg/kg in obese patients was not worse than non-obese patients receiving epileptic treatment.

References:

Clark SL, Leloux MR, Dierkhising RA, et al. IV fosphenytoin in obese patients: dosing strategies, safety, and efficacy. Neurol Clin Pract. 2017;7(1):45-52. doi:10.1212/CPJ.0000000000000322

Phenytoin Disposition in Obesity - Determination of Loading Dose
Design	Prospective study N= 24
Objective	To report the effects of obesity on the disposition of phenytoin
Study Groups	Obese (n= 14) Normal weight (n= 10)
Inclusion Criteria	Patients having received 300 mg of phenytoin sodium
Exclusion Criteria	Not explicitly specified.
Methods	Patients received 300 mg of phenytoin by ten-minute intravenous (IV) infusion. Obese patients had weight >120% of ideal body weight (IBW). The Control group included 10 patients of normal IBW.
Duration	N/A
Outcome Measures	Phenytoin kinetics
Baseline Characteristics		Obese (n= 14)	Normal weight (n= 10)	p-value
	Age, years	37 ± 4	35 ± 3	-
	Male	11 (78.6%)	8 (80.0%)	-
	Total body weight, kg	124 ± 10	67 ± 3	<0.001
	Percent ideal body weight	178 ± 12	92 ± 2	<0.001
	Smoking, no/yes	10/4	6/4	-
Results	Endpoint	Obese (n= 14)	Normal weight (n= 10)	p-value
	Elimination half-life, hr	19.9 ± 3.1	12.0 ± 0.4	<0.025
	Vd, L	82.2 ± 7.9	40.2 ± 1.9	<0.001
	Vdss, L	80.5 ± 7.2	39.8 ± 1.9	<0.001
	VD/kg of total body weight, L/kg	0.68 ± 0.03	0.61 ± 0.02	<0.05
	Clearance, mL/min	59 ± 10	39 ± 3	-
	Clearance/kg of total body weight	0.48 ± 0.06	0.58 ± 0.02	-
	Free fraction, %	13.7 ± 0.7	14.7 ± 0.9	-
Adverse Events	N/A
Study Author Conclusions	Phenytoin loading dose should be calculated on the basis of IBW plus the product of 1.33 times the excess weight over IBW. Very obese individuals will require large absolute loading doses of phenytoin to rapidly achieve therapeutic drug concentrations.
InpharmD Researcher Critique	This older study only evaluated loading doses in a small patient population. It is suggested that steady-state phenytoin clearance will be lower than single-dose clearance due to saturation of biotransformation capacity, resulting in maintenance doses that do not need to be adjusted for body weight.

References:

Abernethy DR, Greenblatt DJ. Phenytoin disposition in obesity. Determination of loading dose. Arch Neurol. 1985;42(5):468-471. doi:10.1001/archneur.1985.04060050066010