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Caspofungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-Abdominal Infections: A Prospective Cohort Study

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Abstract

Objectives

The aim of this study was to report the pharmacokinetics (PK) of caspofungin in plasma and peritoneal fluid and to identify optimal dosing strategies in septic patients with intra-abdominal infections.

Methods

Eleven patients with secondary peritonitis with septic shock received the standard dosing regimen of caspofungin. Total caspofungin plasma and peritoneal concentrations were subject to a population PK analysis using Pmetrics®. Monte Carlo simulations were performed considering the ratio of 24-h total drug exposure above the minimum inhibitory concentration (AUC24/MIC) in plasma and comparing simulated concentrations versus MIC in peritoneal fluid.

Results

Fat-free mass (FFM) was retained in the final model of caspofungin, reporting a total clearance (standard deviation) of 0.78 (0.17) L/h and a central volume of distribution of 9.36 (2.61) L. The peritoneal fluid/plasma ratio of caspofungin was 33% on the first day of therapy (AUC24 73.92 (21.93) and 26.03 (9.88) mg*h/L for plasma and peritoneal data, respectively). Dosing simulations supported the use of standard dosing regimens for patients with an FFM < 50 kg for the most susceptible candida species (C. albicans and C. glabrata). For higher FFM, a loading dose of 70 or 100 mg, with a maintenance dose of 70 mg, reached AUC24/MIC ratios for these species.

Conclusions

There is moderate penetration of caspofungin into the peritoneal cavity (33%). For empirical treatment, a dose escalation of 100 mg loading dose on the first day is suggested for higher FFM to ensure adequate concentrations into the abdominal cavity for the most susceptible candida species.

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Author information

Authors and Affiliations

  1. Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France

    Nicolas Garbez, Laurent Muller, Jean-Yves Lefrant & Claire Roger

  2. Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France

    Nicolas Garbez & Litaty C. Mbatchi

  3. UR-UM 103: IMAGINE (Initial Management And prévention of orGan failures IN critically ill patiEnts), Faculté de médecine, Université de Montpellier, Montpellier, France

    Nicolas Garbez, Laurent Muller, Jeffrey Lipman, Jason A. Roberts, Jean-Yves Lefrant & Claire Roger

  4. Laboratoire de Biochimie, Centre Hospitalier Universitaire (CHU) of Nîmes, Hôpital Carémeau, Nîmes, France

    Litaty C. Mbatchi

  5. UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia

    Steven C. Wallis, Jeffrey Lipman & Jason A. Roberts

  6. Department of Intensive Care Medicine, Royal Brisbane and Womens’ Hospital, Brisbane, QLD, Australia

    Jeffrey Lipman & Jason A. Roberts

  7. Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia

    Jason A. Roberts

  8. Pharmacy Department, Royal Brisbane and Womens’ Hospital, Brisbane, QLD, Australia

    Jason A. Roberts

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  1. Nicolas Garbez
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  4. Laurent Muller
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  8. Claire Roger
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Corresponding author

Correspondence to Nicolas Garbez.

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Funding

This study was supported by academic funding from the Nimes University Hospital (LOCAL/2016/CR-01).

Conflicts of interest/Competing interests

Jeffrey Lipman received honoraria from MSD and Pfizer and also received institution support from MSD. Claire Roger received consultancy fees from MSD, Pfizer, and Fresenius Medical Care. Nicolas Garbez, Litaty C. Mbatchi, Steven C. Wallis, Laurent Muller, Jason A. Roberts, and Jean-Yves Lefrant have no conflicts of interest to declare.

Ethics approval

Ethics approval was obtained from the local ethics committee of Nîmes (Comité de Protection des Personnes Sud-Méditerranée III 2012.02.05).

Consent to participate

Written informed consent was obtained from either the patient or their designated substitute decision maker.

Code availabitity

Pmetrics software package for R (Los Angeles, CA, USA) [32, 33].

Author contributions

CR, J-YL, and LM conceived and designed the study. CR collected data and SCW performed drug assay. NG, CR, J-YL, and JAR analysed data. NG carried out the pharmacokinetic analysis. NG, CR and LM drafted the manuscript. All authors read and approved the final manuscript.

Consent for publication

All patients provided consent for publication of their pooled, anonymized data.

Availability of data and materials

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Supplementary Information

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Garbez, N., Mbatchi, L.C., Wallis, S.C. et al. Caspofungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-Abdominal Infections: A Prospective Cohort Study. Clin Pharmacokinet 61, 673–686 (2022). https://doi.org/10.1007/s40262-021-01062-6

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