Population pharmacokinetic analysis of ropivacaine and its metabolite 2 ',6 '-pipecoloxylidide from pooled data in neonates, infants, and children
ABSTRACT The aim was to characterize ropivacaine and 2',6'-pipecoloxylidide (PPX) pharmacokinetics and factors affecting them in paediatric anaesthesia.
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.
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.
Ropivacaine and PPX unbound clearance depends on body weight and age. The results support approved dose recommendations of ropivacaine for the paediatric population.
- Clinical Pharmacokinetics 06/1996; 30(5):329-32. DOI:10.2165/00003088-199630050-00001 · 5.49 Impact Factor
Article: Pediatric epidural analgesia (PEA).[Show abstract] [Hide abstract]
ABSTRACT: The pediatric epidural is an accepted method of advanced analgesia in children. Newer techniques have now superseded pediatric epidural analgesia (PEA), being as effective and safer, especially with the advances in ultrasonography. PEA is, however, still an important technique to master and employ, and it may be that the indications for this mode of analgesia have now become more defined.Pediatric Anesthesia 01/2012; 22(1):51-5. DOI:10.1111/j.1460-9592.2011.03731.x · 1.74 Impact Factor
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ABSTRACT: Because of its slow systemic absorption and flip-flop kinetics, ropivacaine's pharmacokinetics after a peripheral nerve block has never been thoroughly characterized. The purpose of this study was to develop a population pharmacokinetic model for ropivacaine after loco-regional administration and to identify patient characteristics that may influence the drug's absorption and disposition. Frequent plasma samples were taken up to 93 h after a 100 mg dose given as femoral block for postoperative analgesia in 15 orthopedic patients. Ropivacaine plasma concentration-time data were analyzed using a nonlinear mixed effects modeling method. A one-compartment model with parallel inverse Gaussian and time-dependent inputs best described ropivacaine plasma concentration-time curves. Ropivacaine systemic absorption was characterized by a rapid phase (mean absorption time of 25 ± 4.8 min) followed by a much slower phase (half-life of 3.9 ± 0.65 h). Interindividual variability (IIV) for these parameters, 58 and 9 %, indicated that the initial absorption phase was more variable. The apparent volume of distribution (V/F = 77.2 ± 11.5 L, IIV = 26 %) was influenced by body weight (Δ 1.49 % per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Δ 2.25 % per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8 ± 1.0 L/h, 34 IIV = 34 %). These findings support our hypothesis that modeling a complex systemic absorption directly from plasma concentration-time curves exhibiting flip-flop kinetics is possible. Only the age-effect was considered as relevant for possible dosing adjustments.Journal of Pharmacokinetics and Biopharmaceutics 09/2012; DOI:10.1007/s10928-012-9275-z · 1.46 Impact Factor