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.
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ABSTRACT: The pharmacodynamics of absorption of local anaesthetics used during surgical procedures into tissues is governed by the amount of free drug in plasma. Toxicity may occur during continuous infusions if the levels of free drug become too high which may occur if the binding capacity of the α-1- acid glycoprotein present in plasma is exceeded. In order to monitor this a method was developed for the determination of the amount of free and bound ropivacaine in human plasma during knee and hip surgery. Rapid equilibrium dialysis units were used to separate free and bound drug then protein and buffer salts were removed by solvent precipitation. Analysis was carried out using a ZICHILIC HPLC column interfaced with an LTQ Orbitrap mass spectrometer. The following extracted ion ranges ([M+H](+)) were monitored: m/z 275.21-275.22 for ropivacaine and m/z 235.175-235.185 for lidocaine. The method was calibrated by spiking ropivacaine, and a fixed amount of lidocaine as internal standard, into plasma over the range 0.01-1.5µg/ml. The equation of the line was y=0.886x±4.2% (n=2), forcing the curve through zero since blank plasma was free of the analyte. The values obtained for the accuracy and precision of the analysis of plasma spiked at 0.03µg/ml and 1.5µg/ml were 93.2%±2.8% and 95.4%±1.5% respectively (n=5). Repeat analysis of a patient sample for free and bound drug gave the following values for levels of ropivacaine: bound 1.63µg/ml±1.48%, unbound 0.0671µg/ml±1.68% (n=5).Talanta 12/2013; 117C:60-63. DOI:10.1016/j.talanta.2013.08.049 · 3.50 Impact Factor
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ABSTRACT: The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.Journal of Pharmaceutical Sciences 09/2013; 102(9). DOI:10.1002/jps.23574 · 3.13 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 · 2.06 Impact Factor