title: Steady-state pharmacokinetic simulation of intermittent vs. continuous infusion valproic acid therapy in non-critically ill and critically ill patients.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Clinical Pharmacy , University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences , Aurora , CO , USA.|b Department of Pharmacy , University of Colorado Hospital , Aurora , CO , USA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Van Matre
authors.affiliation: c Department of Pharmacy , University of Kentucky HealthCare , Lexington , KY , USA.|d Department of Pharmacy Practice & Science , University of Kentucky College of Pharmacy , Lexington , KY , USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cook
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015331:Cohort Studies; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D011336:Probability; D012189:Retrospective Studies; D013997:Time Factors; D014635:Valproic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid
keywords: Continuous infusion; Critically ill; Pharmacodynamics; Pharmacokinetics; Status epilepticus; Status migrainosus; Valproic acid