Population pharmacokinetic analysis of ropivacaine and its metabolite 2',6'-pipecoloxylidide from pooled data in neonates, infants, and children

Br J Anaesth. 2011 Sep;107(3):409-24. doi: 10.1093/bja/aer154. Epub 2011 Jun 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amides / pharmacokinetics*
  • Anesthetics, Local / pharmacokinetics*
  • Body Weight
  • Bupivacaine / analogs & derivatives*
  • Bupivacaine / pharmacokinetics
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Metabolic Clearance Rate
  • Models, Biological
  • Orosomucoid / metabolism
  • Protein Binding
  • Ropivacaine


  • Amides
  • Anesthetics, Local
  • Orosomucoid
  • Ropivacaine
  • 2',6'-pipecoloxylidide
  • Bupivacaine