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A population pharmacokinetic model for the complex systemic absorption of ropivacaine after femoral nerve block in patients undergoing knee surgery

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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.

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Acknowledgments

This work was supported by the Canadian Institutes for Heath Research (MOP-84519) and by the Fonds de la Recherche en Santé du Québec (F. Gaudreault’s studentship). The authors are grateful to Johanne Couture from Université de Montréal and Nadia Godin from Hôpital Maisonneuve-Rosemont for their technical support. The authors would like to recognize the contributions of Jun Li at Université de Montréal and John Clements at Merck during model development. We also want to thank Dr. Louis-Philippe Fortier, Dr. Issam Tanoubi and Dr. Bruno Petit at Hôpital Maisonneuve-Rosemont for their precious collaboration in the clinical part.

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Authors and Affiliations

  1. Faculty of Pharmacy, Université de Montréal, P.O. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada

    François Gaudreault & France Varin

  2. Department of Anesthesiology, Maisonneuve-Rosemont Hospital and Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Pierre Drolet

  3. Department of Orthopedic Surgery, Maisonneuve-Rosemont Hospital and Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Michel Fallaha

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  1. François Gaudreault
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  2. Pierre Drolet
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  3. Michel Fallaha
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  4. France Varin
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Correspondence to France Varin.

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Gaudreault, F., Drolet, P., Fallaha, M. et al. A population pharmacokinetic model for the complex systemic absorption of ropivacaine after femoral nerve block in patients undergoing knee surgery. J Pharmacokinet Pharmacodyn 39, 635–642 (2012). https://doi.org/10.1007/s10928-012-9275-z

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  • DOI: https://doi.org/10.1007/s10928-012-9275-z

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