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Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

Ropivacaine has an optimal toxicity profile for epidural anesthesia in adults, but there are currently no studies concerning its pharmacokinetics during continuous infusion. The primary objective of this study was to evaluate the pharmacokinetics and safety of ropivacaine in adults during a 48-h continuous epidural infusion.

Materials and methods

We enrolled 43 adults (ASA I-II) scheduled for major abdominal or urologic surgery with postoperative continuous epidural analgesia with ropivacaine 0.2% (5 mL/h) and sufentanil 0.75 μg/mL for 48 h. Ropivacaine blood samples were collected during continuous epidural infusion before the bolus and 3, 6, 12, 24, 48, 54, 60 h after the bolus; plasma concentrations were measured on HPLC-UV. The concentration-time relationship of ropivacaine levels was analyzed using a population pharmacokinetic method based on a mixed-effect-model approach (P-PHARM software).

Results

Mean plasma concentration of ropivacaine at the end of epidural infusion (C48h) was 1.69 μg/mL (0.21–3.8 μg/mL). Mean (range) Cmax was 1.82 μg/mL (0.61–4.0 μg/mL); the area under the plasma concentration curve, AUC (0-60), was 67.48 ± 30.60 μg·h/mL. Total plasma ropivacaine concentrations fell mainly within (84%) or below (12%) the range reported to be safe in adults (1.0–3.0 μg/mL). Only two patients (5%) reached ropivacaine plasma levels higher than 3 μg/mL, namely 3.8 and 4.0 μg/mL at 48 and 54 h, respectively. Total ropivacaine concentrations up to 4.0 μg/mL were tolerated during long-term epidural ropivacaine infusion. Mean clearance for total ropivacaine was 5.33 L/h. Age was the only covariable to significantly reduce clearance variability: CL (L/h) = 15.04 − 0.148 × age (years). The volume of distribution (Vd) was 92.15 L. The infusion dosing period half-life (t1/2,DP = 0.693 × Vd/CL) was 10.8 h.

Conclusions

Exposure to ropivacaine during epidural infusion is highly variable. The apparent infusion dosing half-life t1/2,DP is the most appropriate parameter to predict drug accumulation upon epidural infusion since it appears to better reflect the interplay interference between volume distribution and absorption rate during the accumulation phase. Prediction of ropivacaine accumulation can be improved by considering patient age.

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Acknowledgements

This research is supported by a grant from the Foundation IRCCS Policlinico San Matteo, Pavia, Italy.

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Authors and Affiliations

  1. Laboratory of Clinical Pharmacokinetics, Foundation IRCCS Policlinico San Matteo, P.le Golgi, 2, I-27100, Pavia, Italy

    Maria Cusato, Monica Broglia & Mario Regazzi

  2. Department of Anesthesia and Intensive Care I and Pain Therapy, Foundation IRCCS Policlinico San Matteo, Pavia, Italy

    Massimo Allegri, Tekla Niebel & Antonio Braschi

  3. Department of Surgical Science, Pavia University, Pavia, Italy

    Tekla Niebel

  4. First Service of Anesthesia and Intensive Care, San Gerardo Hospital Monza (MI) – Department of Experimental Medicine, Milan-Bicocca University, Milan, Italy

    Pablo Ingelmo

  5. Department of Resuscitation and Organ Transplantation Surgery Sciences, Section of Anesthesiology and Resuscitation, University of Pavia, Pavia, Italy

    Antonio Braschi

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  1. Maria Cusato
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  2. Massimo Allegri
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  3. Tekla Niebel
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  7. Mario Regazzi
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Correspondence to Mario Regazzi.

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Cusato, M., Allegri, M., Niebel, T. et al. Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate. Eur J Clin Pharmacol 67, 399–406 (2011). https://doi.org/10.1007/s00228-010-0927-x

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  • DOI: https://doi.org/10.1007/s00228-010-0927-x

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