title: Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures.
abstract: OBJECTIVE
  The application of lidocaine (lignocaine) as an anticonvulsant in neonates originated more than 40 years ago in Scandinavia. Lidocaine has been shown to be an effective anticonvulsant for the treatment of neonatal seizures that persist in spite of first-line anticonvulsant therapy. However, lidocaine toxicity, mainly in the form of cardiac arrhythmias, can be life threatening. Therapeutic drug monitoring can be useful to prevent toxicity. In a previous study, a dosing regimen was developed for term neonates, but it was not evaluated for preterm neonates. Extrapolation of the previously developed dosing regimen to premature neonates without accounting for differences in pharmacokinetics because of immaturity of phase I metabolism and body fat/water ratio may result in serious toxicity or therapy failure. The objective of this study was to develop an optimized dosing regimen for lidocaine in preterm as well as term neonates, using population pharmacokinetic modelling and simulation.
  
  
  METHODS
  The requirements for this dosing regimen were simplicity of implementation, equal initial doses for all weight categories and avoidance of plasma concentrations >9 mg/L. After lidocaine administration, blood samples were collected from an arterial line from a total of 46 preterm and term neonates with convulsion, within 10 days after birth. Lidocaine concentrations were measured in plasma using a fluorescence polarization immunoassay. Population pharmacokinetic modelling started with assessment of two important aspects of paediatric pharmacokinetics: relation to body size and the effects of maturation.
  
  
  RESULTS
  In the studied neonatal population (term and preterm neonates with gestational ages up to 10 days), gestational age and bodyweight were closely related. Therefore, the effects of allometry and maturation on lidocaine pharmacokinetics could not be described independently and were described by a combined power estimate of bodyweight on clearance and volume of distribution. Based on this pharmacokinetic model, a dosing strategy for lidocaine for neonatal seizure control was developed, which allows rapid and safe administration of lidocaine in this population. When prospective validation confirms our model, routinely performed therapeutic drug monitoring should no longer be necessary and would only be advised in cases of (suspected) clinical symptoms of over- or underdosing.
  
  
  CONCLUSIONS
  A lidocaine dosing regimen for seizure control in preterm and term neonates has been developed using population pharmacokinetic modelling and simulation. Allometry and maturation exponents were combined into one exponent for each pharmacokinetic parameter and could not be described independently. Based on this model, this regimen allows rapid and safe administration of lidocaine in this population.
authors.affiliation: Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands. m.p.h.vandenbroek@umcutrecht.nl
authors.forename: Marcel P H
authors.initials: MP
authors.lastname: van den Broek
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Johan G C
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: Floris
authors.initials: F
authors.lastname: Groenendaal
authors.forename: Mona C
authors.initials: MC
authors.lastname: Toet
authors.forename: Toine C G
authors.initials: TC
authors.lastname: Egberts
authors.forename: Linda S
authors.initials: LS
authors.lastname: de Vries
authors.forename: Catharine M A
authors.initials: CM
authors.lastname: Rademaker
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002985:Clinical Protocols; D016903:Drug Monitoring; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000188:drug therapy; D008012:Lidocaine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D015233:Models, Statistical; D012537:Scandinavian and Nordic Countries; D012640:Seizures / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D008012:Lidocaine