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Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia

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Abstract

Background

Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown.

Objective

The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia.

Methods

Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2. Uncertainty of parameters was estimated by bootstrapping.

Results

Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two-compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E max model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics.

Conclusions

This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight.

Study Registration

This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de Sécurité du Médicament et des Produits de Santé ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France).

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Acknowledgments

We thank medical staff who collected the data of the study. We thank laboratory staff of pharmacology that performed plasma determination. We thank Lixoft Company to provide us the academic user license. We thank Prof Nick Holford to provide us wings usable with Monolix software.

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Authors and Affiliations

  1. Department of Pharmacology, EA3801, SFR CAP-Santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095, Reims Cedex, France

    Zoubir Djerada, Catherine Feliu, Yoann Cazaubon & Jean-Marc Malinovsky

  2. Department of Anaesthesia and Intensive Care Pole URAD, Reims University Hospital, 45, rue Cognacq-Jay, 51092, Reims Cedex, France

    Faouzi Smati, Philippe Gomis, Beny Charbit, Olivier Fernandes & Jean-Marc Malinovsky

  3. Department of Nephrology and Transplantation, Centre, Rouen, France

    Dominique Guerrot

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  1. Zoubir Djerada
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Contributions

Z.D. designed the study, study execution and data acquisition, developed and implemented the PK/PD models in MONOLIX, data analysis and interpretation, graphical representation, and wrote the first draft of the manuscript. C.F., Y.C., DG: data acquisition, data interpretation, graphical representation, and revised critically the manuscript for content and gave final approval to the manuscript version submitted for publication. F.S., P.G., B.C., O.F. performed the volunteer recruitment, data interpretation, and revised critically the manuscript for content and gave final approval to the manuscript version submitted for publication. J.J.M.: designed the study, study execution and data acquisition, performed recruitment, data analysis and interpretation, revised critically the manuscript for content and gave final approval to the manuscript version submitted for publication.

Corresponding author

Correspondence to Zoubir Djerada.

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Funding

This study was funded by the Regional Clinical Research Program of Reims University Hospital, in 2004 (PHRC 2005).

Conflict of interest

Z.D., C.F., Y.C., D.G, F.S., P.G., B.C., O.F., J.J.M. declare no financial relationships with any organisations that might have an interest in the submitted work; no other relationships or activities that could appear to have influenced the submitted work.

Electronic supplementary material

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40262_2017_617_MOESM1_ESM.jpg

Electronic Supplementary Fig. 1 Diagnostic plots. Population (blue dot) or individual (black circle) weighted residuals (PWRES or IWRES) versus time of ropivacaine concentration (a) and sensory block level (b), PWRES or IWRES versus respective predictions of ropivacaine concentration (c) and sensory block level (d)

40262_2017_617_MOESM2_ESM.jpg

Electronic Supplementary Fig. 2 Diagnostic plots. Observed ropivacaine concentrations versus population-predicted ropivacaine concentrations (a). Observed sensory block level versus population-predicted sensory block level (b)

Supplementary material 3 (DOCX 18 kb)

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Djerada, Z., Feliu, C., Cazaubon, Y. et al. Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia. Clin Pharmacokinet 57, 1135–1147 (2018). https://doi.org/10.1007/s40262-017-0617-2

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