Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex

Ann Pharmacother. 2019 May;53(5):458-463. doi: 10.1177/1060028018818785. Epub 2018 Dec 7.

Abstract

Background: Recommended loading doses (LDs) of phenytoin and fosphenytoin range from 10 to 25 mg/kg. Few studies have examined the LD requirements in male versus female patients and in patients who are obese.

Objectives: To examine the influence of obesity and sex on phenytoin LDs.

Methods: This was a retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following LDs in male versus female and nonobese versus obese patients. An equation used for determining LDs in obese patients was evaluated.

Results: There were 141 nonobese and 54 obese patients. When adjusted for total body weight, the obese cohort received a smaller LD than the nonobese cohort (17 mg/kg, interquartile range [IQR] = 14.9-20.0, vs 20 mg/kg, IQR = 18.6-20.0, respectively; P < 0.001). There was no difference between the 2 cohorts in the measured free phenytoin concentration following the LD (obese: 1.7 µg/mL [IQR = 1.4-2.0]; nonobese: 1.8 µg/mL [IQR = 1.5-2.1]; P = 0.16). In the obese cohort, men received a significantly lower weight-based phenytoin dose compared with women (15 mg/kg [IQR = 14.0-19.2], vs 19.9 mg/kg [IQR = 15.0-20.0], respectively; P = 0.008). Postload free phenytoin concentrations were similar between the 2 groups (male: 1.6 µg/mL [IQR = 1.2-2.1]; female: 1.7 µg/mL [IQR = 1.4-2.0]; P = 0.24). Conclusion and Relevance: Phenytoin and fosphenytoin LDs of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations.

Keywords: anticonvulsants; dosing; obesity; pharmacokinetics; seizures.

MeSH terms

  • Administration, Intravenous
  • Adult
  • Aged
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / pharmacokinetics
  • Body Mass Index
  • Dose-Response Relationship, Drug
  • Drug Dosage Calculations*
  • Epilepsy / complications
  • Epilepsy / drug therapy*
  • Epilepsy / epidemiology
  • Epilepsy / metabolism
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Obesity / complications*
  • Obesity / drug therapy
  • Obesity / epidemiology
  • Obesity / metabolism
  • Phenytoin / administration & dosage
  • Phenytoin / analogs & derivatives*
  • Phenytoin / pharmacokinetics
  • Retrospective Studies
  • Sex Factors

Substances

  • Anticonvulsants
  • Phenytoin
  • fosphenytoin