Steady-state pharmacokinetic simulation of intermittent vs. continuous infusion valproic acid therapy in non-critically ill and critically ill patients

Edward Van Matre, Aaron M. Cook

Research output: Contribution to journalArticle

Abstract

Objectives: Valproic acid (VPA) is a broad-spectrum antiepileptic drug used for a variety of neurologic disorders. The relatively short half-life seen with intermittent intravenous bolus doing may lead to serum concentration variability. Continuous infusion VPA therapy is an approach to mitigate these effects. The objective of this study is to characterize the pharmacokinetics of continuous infusion of VPA in acutely ill patients and to determine dosing regimens that most frequently obtain goal steady-state serum concentrations. Methods: This is a retrospective pharmacokinetics study in adult patients receiving continuous infusion VPA per institutional protocol for seizure or status migrainosus. Pharmacokinetic parameters were reviewed for 234 patients (25 critically ill) and compared between the two groups (non-critically ill vs. critically ill). Intermittent and continuous infusion dosing strategies were modeled utilizing Monte Carlo simulations for both cohorts. Frequencies of serum concentration attainment were reported. Results: The percent target attainment for the non-critically ill group and critically ill group were 69.4 and 58.3% (p = 0.282) post-loading dose and 69.7 and 37.5% (p = 0.004) steady state, respectively. The volume of distribution was significantly different between the two groups (0.35 vs. 0.68 L/kg, p = < 0.0001). Highest frequency of target attainment (50–100 mcg/ml) occurred in the continuous infusion 2 mg/kg/h simulation for both critically ill (45.19%) and acutely ill (48.16%) groups. Discussion: Critically ill patients have an increased volume of distribution. Increasing the volume of distribution requires higher loading doses of VPA to obtain desired therapeutic concentrations. Continuous infusion VPA provides more consistent serum steady-state concentrations while mitigating pharmacokinetic variability.

Original languageEnglish (US)
Pages (from-to)786-791
Number of pages6
JournalNeurological Research
Volume38
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Valproic Acid
Critical Illness
Pharmacokinetics
Serum
Therapeutics
Nervous System Diseases
Migraine Disorders
Anticonvulsants
Half-Life
Seizures
Retrospective Studies

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Neurology
  • Clinical Neurology

Cite this

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title = "Steady-state pharmacokinetic simulation of intermittent vs. continuous infusion valproic acid therapy in non-critically ill and critically ill patients",
abstract = "Objectives: Valproic acid (VPA) is a broad-spectrum antiepileptic drug used for a variety of neurologic disorders. The relatively short half-life seen with intermittent intravenous bolus doing may lead to serum concentration variability. Continuous infusion VPA therapy is an approach to mitigate these effects. The objective of this study is to characterize the pharmacokinetics of continuous infusion of VPA in acutely ill patients and to determine dosing regimens that most frequently obtain goal steady-state serum concentrations. Methods: This is a retrospective pharmacokinetics study in adult patients receiving continuous infusion VPA per institutional protocol for seizure or status migrainosus. Pharmacokinetic parameters were reviewed for 234 patients (25 critically ill) and compared between the two groups (non-critically ill vs. critically ill). Intermittent and continuous infusion dosing strategies were modeled utilizing Monte Carlo simulations for both cohorts. Frequencies of serum concentration attainment were reported. Results: The percent target attainment for the non-critically ill group and critically ill group were 69.4 and 58.3{\%} (p = 0.282) post-loading dose and 69.7 and 37.5{\%} (p = 0.004) steady state, respectively. The volume of distribution was significantly different between the two groups (0.35 vs. 0.68 L/kg, p = < 0.0001). Highest frequency of target attainment (50–100 mcg/ml) occurred in the continuous infusion 2 mg/kg/h simulation for both critically ill (45.19{\%}) and acutely ill (48.16{\%}) groups. Discussion: Critically ill patients have an increased volume of distribution. Increasing the volume of distribution requires higher loading doses of VPA to obtain desired therapeutic concentrations. Continuous infusion VPA provides more consistent serum steady-state concentrations while mitigating pharmacokinetic variability.",
author = "{Van Matre}, Edward and Cook, {Aaron M.}",
year = "2016",
month = "9",
day = "1",
doi = "10.1080/01616412.2016.1206164",
language = "English (US)",
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pages = "786--791",
journal = "Neurological Research",
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publisher = "Maney Publishing",
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TY - JOUR

T1 - Steady-state pharmacokinetic simulation of intermittent vs. continuous infusion valproic acid therapy in non-critically ill and critically ill patients

AU - Van Matre, Edward

AU - Cook, Aaron M.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Objectives: Valproic acid (VPA) is a broad-spectrum antiepileptic drug used for a variety of neurologic disorders. The relatively short half-life seen with intermittent intravenous bolus doing may lead to serum concentration variability. Continuous infusion VPA therapy is an approach to mitigate these effects. The objective of this study is to characterize the pharmacokinetics of continuous infusion of VPA in acutely ill patients and to determine dosing regimens that most frequently obtain goal steady-state serum concentrations. Methods: This is a retrospective pharmacokinetics study in adult patients receiving continuous infusion VPA per institutional protocol for seizure or status migrainosus. Pharmacokinetic parameters were reviewed for 234 patients (25 critically ill) and compared between the two groups (non-critically ill vs. critically ill). Intermittent and continuous infusion dosing strategies were modeled utilizing Monte Carlo simulations for both cohorts. Frequencies of serum concentration attainment were reported. Results: The percent target attainment for the non-critically ill group and critically ill group were 69.4 and 58.3% (p = 0.282) post-loading dose and 69.7 and 37.5% (p = 0.004) steady state, respectively. The volume of distribution was significantly different between the two groups (0.35 vs. 0.68 L/kg, p = < 0.0001). Highest frequency of target attainment (50–100 mcg/ml) occurred in the continuous infusion 2 mg/kg/h simulation for both critically ill (45.19%) and acutely ill (48.16%) groups. Discussion: Critically ill patients have an increased volume of distribution. Increasing the volume of distribution requires higher loading doses of VPA to obtain desired therapeutic concentrations. Continuous infusion VPA provides more consistent serum steady-state concentrations while mitigating pharmacokinetic variability.

AB - Objectives: Valproic acid (VPA) is a broad-spectrum antiepileptic drug used for a variety of neurologic disorders. The relatively short half-life seen with intermittent intravenous bolus doing may lead to serum concentration variability. Continuous infusion VPA therapy is an approach to mitigate these effects. The objective of this study is to characterize the pharmacokinetics of continuous infusion of VPA in acutely ill patients and to determine dosing regimens that most frequently obtain goal steady-state serum concentrations. Methods: This is a retrospective pharmacokinetics study in adult patients receiving continuous infusion VPA per institutional protocol for seizure or status migrainosus. Pharmacokinetic parameters were reviewed for 234 patients (25 critically ill) and compared between the two groups (non-critically ill vs. critically ill). Intermittent and continuous infusion dosing strategies were modeled utilizing Monte Carlo simulations for both cohorts. Frequencies of serum concentration attainment were reported. Results: The percent target attainment for the non-critically ill group and critically ill group were 69.4 and 58.3% (p = 0.282) post-loading dose and 69.7 and 37.5% (p = 0.004) steady state, respectively. The volume of distribution was significantly different between the two groups (0.35 vs. 0.68 L/kg, p = < 0.0001). Highest frequency of target attainment (50–100 mcg/ml) occurred in the continuous infusion 2 mg/kg/h simulation for both critically ill (45.19%) and acutely ill (48.16%) groups. Discussion: Critically ill patients have an increased volume of distribution. Increasing the volume of distribution requires higher loading doses of VPA to obtain desired therapeutic concentrations. Continuous infusion VPA provides more consistent serum steady-state concentrations while mitigating pharmacokinetic variability.

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U2 - 10.1080/01616412.2016.1206164

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JF - Neurological Research

SN - 0161-6412

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