title: Population pharmacokinetic analysis of ropivacaine and its metabolite 2',6'-pipecoloxylidide from pooled data in neonates, infants, and children.
abstract: BACKGROUND
  The aim was to characterize ropivacaine and 2',6'-pipecoloxylidide (PPX) pharmacokinetics and factors affecting them in paediatric anaesthesia.
  
  
  METHODS
  Population pharmacokinetics of ropivacaine and its active metabolite PPX were estimated after single and continuous ropivacaine blocks in 192 patients aged 0-12 yr from six pooled published studies. Unbound and total ropivacaine and PPX plasma concentration and PPX urinary excretion data were used for non-linear mixed-effects modelling by NONMEM. Covariates included age, body weight, gender, ethnic origin, ASA, site and method of administration, and total dose.
  
  
  RESULTS
  One-compartment first-order pharmacokinetic models incorporating linear binding of ropivacaine and PPX to α(1)-acid glycoprotein were used. After accounting for the effect of body weight, clearance of unbound ropivacaine and PPX reached 41% and 89% of their mature values, respectively, at the age of 6 months. Ropivacaine half-life decreased with age from 13 h in the newborn to 3 h beyond 1 yr. PPX half-life differed from 19 h in the newborn to 8-11 h between 1 and 12 months to 17 h after 1 yr. Simulations indicate that for a single caudal block, the recommended dose could be increased by a factor of 2.9 (0-1 month group) and 6.3 (1-12 yr group) before the unbound plasma concentrations would cross the threshold for systemic toxicity. Corresponding factors for continuous epidural infusion are 1.8 and 4.9.
  
  
  CONCLUSIONS
  Ropivacaine and PPX unbound clearance depends on body weight and age. The results support approved dose recommendations of ropivacaine for the paediatric population.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
authors.forename: L
authors.initials: L
authors.lastname: Aarons
authors.forename: B
authors.initials: B
authors.lastname: Sadler
authors.forename: M
authors.initials: M
authors.lastname: Pitsiu
authors.forename: J
authors.initials: J
authors.lastname: Sjövall
authors.forename: J
authors.initials: J
authors.lastname: Henriksson
authors.forename: V
authors.initials: V
authors.lastname: Molnár
mesh_terms: D000367:Age Factors; D000577:Amides / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000493:pharmacokinetics*; D001835:Body Weight; D002045:Bupivacaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D000077212:Ropivacaine
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D009961:Orosomucoid; D000077212:Ropivacaine; C025149:2',6'-pipecoloxylidide; D002045:Bupivacaine