@inproceedings{8768263,
  abstract     = {{Objectives: Calibration is an essential aspect of microdialysis research. In drug trials, retrodialysis by drug (RD) and retrodialysis by internal calibrator (RC) are the most frequently used calibration techniques. In this study, we aimed (1) to evaluate these calibration techniques for piperacillin (PIP) - tazobactam (TAZ) by comparing the recovery rates (RRs) during RD and RC, both in vitro and in vivo, and (2) to assess the reliability of in vitro to in vivo extrapolation of microdialysis methodology and RR for PIP-TAZ.
Methods: Microdialysis catheters with a membrane length of 10 mm were used. The flow rate was set to 2 µL/min. During RD both PIP and TAZ were added to the perfusion solution (NaCl 0,9%). Benzylpenicillin was chosen as internal calibrator for PIP and TAZ. This methodology was first tested in vitro and was subsequently applied in a preclinical study in sixteen piglets and a clinical study in five pediatric intensive care (PICU) patients. Both calibration techniques were performed in each animal and study patient. Microdialysis catheters were placed in the paraspinal and thigh muscle, respectively. Data are reported as mean ± standard deviation.
Results: Following the in vitro experiments, both RD and RC were deemed successful for PIP and TAZ, with mean RRs of 47 ± 6% (PIP) and 59 ± 5% (TAZ) for RD and 52 ± 5% for RC. In the piglet study, in general, RC recovery (29 ± 10%) rendered higher RRs and resulted in more consistent and reliable tissue concentration-time curves than RD (22 ± 10% PIP; 27 ± 11% TAZ). In the first two PICU study patients both calibration techniques performed poorly with very low RRs: 0.2 ± 0.4% (PIP) and 1.5 ± 0.7% (TAZ) for RD and 7 ± 6% for RC. As these discrepancies between the preclinical and clinical in vivo RRs were unexpected, methodological changes were made in the subsequent study patients. Reducing the flow rate from 2 to 1 µL/min led to an important increase of the RR for RC (24 ± 9%), but satisfactory RR for RD could not be reached. Additionally omitting TAZ from the perfusion solution during RD significantly improved the performance of RD for PIP (23 ± 8 %).
Conclusion: We documented that an in vitro optimization of experimental design does not always translate into satisfactory RRs in vivo and thus a successful measurement of tissue concentrations. Also, extrapolation of RRs between different in vivo settings should be done with caution, as was shown by the marked differences in RRs between the preclinical piglet study and initial PICU patients. The finding in the clinical study that simultaneous RD for PIP and TAZ seemed to reduce the loss rate of both compounds, requires further study.}},
  author       = {{Hermans, Eline and Zeitlinger, Markus and Dhont, Evelyn and De Paepe, Peter and Vande Walle, Johan and Devreese, Mathias and De Cock, Pieter}},
  booktitle    = {{9th International Microdialysis Symposium 2022, Abstracts}},
  keywords     = {{microdialysis,microdialysis calibration,piperacillin-tazobactam,tissue pharmacokinetics,juvenile animal model,sepsis,pediatric drug research}},
  language     = {{eng}},
  location     = {{Berlin, Germany}},
  title        = {{The translation from in vitro experiments to in vivo microdialysis trials : a case study of piperacillin-tazobactam}},
  year         = {{2022}},
}