title: Thiopentone elimination in newborn infants: exploring Michaelis-Menten kinetics.
abstract: BACKGROUND
  Thiopentone elimination has been described using Michaelis-Menten pharmacokinetics in adults after prolonged infusion or overdose, but there are few reports of elimination in neonates.
  
  
  METHODS
  Time-concentration profiles for neonates (n=37) given single-dose thiopentone were examined using both first-order (constant clearance) and mixed-order (Michaelis-Menten) elimination processes using nonlinear mixed effects models. These profiles included a 33-week post-menstrual age (PMA) neonate given an overdose. A two-compartment mamillary model was used to fit data. Parameter estimates were standardized to a 70 kg person using allometric models.
  
  
  RESULTS
  There were 197 observations available for analysis from neonates with a mean post-menstrual age of 35 (SD 4.5) weeks and a mean weight of 2.5 (SD 0.9) kg. They were given a mean thiopentone dose of 3 (SD 0.4) mg/kg as a rapid bolus. Clearance at 26 weeks PMA was 0.015 l/min/70 kg and increased to 0.119 l/min/70 kg by 42 weeks PMA. The maximum rate of elimination (V(max)) at 26 weeks PMA was 0.22 mg/min/70 kg and increased to 4.13 mg/min/70 kg by 42 weeks PMA. These parameter estimates are approximately 40% adult values at term gestation. The Michaelis constant (K(m)) was 28.3 [between subject variability (BSV) 46.4%, 95% confidence interval (CI) 4.49-99.2] mg/l; intercompartment clearance was 0.44 (BSV 97.5%, 95% CI 0.27-0.63) l/min/70 kg; central volume of distribution was 46.4 (BSV 29.2%, 95% CI 41.7-59.8) l/70 kg; peripheral volume of distribution was 95.7 (BSV 70.3%, 95% CI 61.3-128) l/70 kg.
  
  
  CONCLUSIONS
  Both first-order and mixed-order processes satisfactorily described elimination. First-order elimination adequately described the time-concentration profile in the premature neonate given an overdose. Clearance is immature in the pre-term neonate although there is rapid maturation around 40 weeks PMA, irrespective of post-natal age.
authors.affiliation: Department of Physiology & Pharmacology, Section of Anaesthesiology & Intensive Care, Karolinska Institute, Stockholm, Sweden. peter.larsson@karolinska.se
authors.forename: P
authors.initials: P
authors.lastname: Larsson
authors.forename: B J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: E
authors.initials: E
authors.lastname: Norman
authors.forename: P
authors.initials: P
authors.lastname: Westrin
authors.forename: V
authors.initials: V
authors.lastname: Fellman
mesh_terms: D000328:Adult; D000465:Algorithms; D001499:Bayes Theorem; D001835:Body Weight / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D062787:Drug Overdose; D005865:Gestational Age; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D007231:Infant, Newborn; D007234:Infant, Premature; D017711:Nonlinear Dynamics; D011153:Population; D013874:Thiopental / Q000493:pharmacokinetics*
chemical_list: D006993:Hypnotics and Sedatives; D013874:Thiopental