Ilia, L. (1,*), Michelet, R. (1,*), Busse, D. (1,2), Simon, P. (3), Dorn, C. (4), Ehmann, L. (1,2), Kloft, C. (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Dept. of Anaesthesiology and Intensive Care Medicine and Integrated Research and Treatment Center (IFB), Adiposity Diseases, University of Leipzig, Germany, (4) Institute of Pharmacy, University of Regensburg, Germany, * shared first authorship
Objectives: Developing and finding the optimal dosing regimen of antiinfectives with the goal of optimising therapeutic outcome and preventing the emergence and spread of resistance remain main challenges in our healthcare system. Knowledge of concentrations at target sites such as interstitial space fluid (ISF) is gaining high attention to predict probability of pharmacokinetic/pharmacodynamics (PK/PD) attainment. This knowledge can be gathered using the minimally invasive microdialysis (µD) sampling technique [1] which is based on passive diffusion of molecules across a semipermeable membrane at the tip of a µD catheter. The catheter is continuously perfused with a drug-free solution (perfusate) that closely resembles the composition of the surrounding tissue fluid at a low flow rate. Unbound drug in the extracellular tissue fluid can be determined by measuring the drug concentration in the collected dialysate. Catheter calibration as retrodialysis needs to be performed to account for relative recovery values less than 100%. However, variability after using in vivo retrodialysis as calibration method remains high, which prompts in vitro investigation to identify and quantify its sources. In this work, the antibiotic linezolid (LIN) was studied in vitro with a focus on the variability in relative recovery and its impact on microdialysate concentrations, compared to in vivo µD.
Methods: An in vivo ISF LIN concentration-time profile (C(t) profile) obtained from the typical patient profile of a clinical µD study [2], [3] was mimicked in a µD system. Samples were taken from the flask which represents the ISF and collected from three different µD catheters (CMA 60, 20 kDa cut-off) simultaneously over eight hours. As calibration method retrodialysis was consecutively performed twice and thrice respectively. This was repeated on four different occasions using the same catheters. Nonlinear mixed-effects (NLME) modelling was performed using NONMEM® (7.4.3) to characterise the LIN C(t) profile in the µD system and to quantify the different levels of variability. An integrated ISF and micro-/retrodialysis modelling approach was chosen to evaluate data from all three available sources (ISF, micro- and retrodialysis) simultaneously [4]. Afterwards, variabilities associated with relative recovery were compared to variability from in vivo clinical data.
Results: The clinical LIN C(t) profile of a typical patient was successfully mimicked by the µD system by optimising pump flow rates and infusion concentrations. The LIN C(t) profile in the in vitro system was successfully described using a one compartmental model with linear clearance for the flask and three µD measurement compartments. The predictive performance of the PK model was adequate and typical parameter estimates (95% CI) were in line with the experimental settings. Estimated ISF-compartment volume and clearance were 91.1 mL (85.1 – 97.0 mL) and 155 µL/min (133 – 167 µL/min), compared to a flask volume of 100 mL and pump rate of 145 µL/min. The typical relative recovery of 91.9% from µD was comparable to the values derived from the retrodialysis experiments (85.1–96.2%). Recovery variability was split up in intracatheter and intercatheter variability which were 2.60%CV (1.97 – 3.23%CV) and 2.80%CV (2.34 – 3.26%CV) respectively, compared to 27.2%CV (21.8 – 32.0%CV) and 26.1%CV (16.7 – 33.8%CV) in vivo.
Conclusion: The established µD system and model-based analysis provide quantitative and qualitative insights into the µD sampling technique, specifically its variabilities, for the case compound LIN. In vitro derived variability was up to ten times lower than in vivo. This suggest that the current in vivo assessment of sources of µD variability might be confounded by other factors such as variability in the conducted retrodialysis experiments or in the sampled target site. An integrated approach considering additional in vitro and in vivo data might identify these confounding factors and thus aid in further elucidating the high variability in clinical µD studies.
References:
[1] Committee for Human Medicinal Products (CHMP). Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antibacterial medicinal products. Eur. Med. Agency (2016).
[2] Ehmann, 26th PAGE, Budapest, Hungary (2017).
[3] P. Simon, D. Petroff, S. Hochstädt, A. Dietrich, C. Kloft, M. Zeitlinger, F. Kees, S. Stehr, H. Wrigge. Einfluss von Adipositas auf Plasma und Gewebespiegel von Linezolid nach Einmalapplikation –Eine kontrollierte klinische Studie. Anästh Intensivmed (2018).
[4] Minichmayr IK, Schaeftlein A, Kuti JL, Zeitlinger M, Kloft C. Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients. Clin. Pharmacokinet. (2016).
Reference: PAGE 28 (2019) Abstr 9134 [www.page-meeting.org/?abstract=9134]
Poster: Drug/Disease Modelling - Infection