Franziska Kluwe (1,2), Malin Ansin (1), Richard Schwameis (3), Daniela Burau (1), Wilhelm Huisinga (4), Markus Zeitlinger (3), Charlotte Kloft (1)
(1) Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training Program PharMetrX, Germany, (3) Department of Clinical Pharmacology, Medical University of Vienna, Austria, (4) Institute of Mathematics, Universitaet Potsdam, Germany
Objectives: Cefuroxime, a broad-spectrum cephalosporin antibiotic, is routinely administered as preoperative prophylaxis during orthopaedic surgery and for the treatment of septic arthritis. Adequate antibiotic concentrations at the target site of an infection are required for effective prophylaxis or therapy. However, information about target-site pharmacokinetics of cefuroxime is still lacking. The microdialysis technique is a minimally invasive, highly sensitive method to investigate antibiotic target-site concentrations. In order to evaluate the pharmacokinetics of cefuroxime after standard dosing in different matrices, including synovial fluid of the knee and interstitial fluid of muscle tissue assessed by microdialysis, the nonlinear mixed-effects modelling approach was used.
Methods: For the model development, data from an open-labelled, single-centre Phase I study (EudraCT: 2012-000379-18), conducted at the Medical University of Vienna, was used [1]. Patients undergoing elective knee arthroscopy (n=10, 8 male, age: 18.7–61.7 years, weight: 58.0–118 kg) received a single postoperative infusion of 1500 mg cefuroxime over 30 min. Plasma samples were taken and microdialysis was performed simultaneously in the synovial space of the knee and in the skeletal muscle of the thigh, using retrodialysis for catheter calibration. For each matrix (synovial fluid, interstitial fluid of muscle tissue and plasma), samples were collected pre-dose (nmedian/matrix=10) and every 30 to 60 min up to 8 h after dosing (nmedian/matrix=110). The samples were quantified via high-performance liquid chromatography and data from all matrices was analysed using R (3.4.3) and NONMEM (7.3.0, with first-order conditional estimation method and interaction option). To assess the model performance, precision of parameter estimates and graphical model evaluation techniques, such as goodness-of-fit plots and visual-predictive checks, were utilised.
Results: A two-compartment pharmacokinetic model with linear elimination adequately described the plasma data. Due to delayed distribution of cefuroxime into the synovial fluid and interstitial fluid of muscle tissue, both –kinetically similarly behaving– matrices were assigned to the peripheral compartment. To account for the extent of cefuroxime distribution into synovial fluid and interstitial fluid of muscle tissue in the model, a tissue distribution factor was estimated for each matrix. Overall, cefuroxime displayed good penetration abilities into both synovial fluid (distribution factor of 1.94) and interstitial fluid of muscle tissue (distribution factor of 1.59) with respect to peripheral concentrations. Cefuroxime clearance was estimated to be 16.5 L/h, the central volume of distribution, intercompartmental clearance and peripheral volume of distribution were 14.2 L, 20.2 L/h and 13.5 L, respectively. Relative recovery estimated during retrodialysis was found to be comparable in interstitial fluid of muscle tissue and in synovial fluid (14.8% and 14.2%). Using an exponential model for random effects, interindividual variability was implemented on clearance, central volume of distribution, relative recovery values and tissue distribution factors, yielding least precise estimates for relative recovery in synovial fluid (67.2 %CV). Residual variability was separately estimated for the different measurement matrices, enabling the dissection of overall residual variability into matrix- and/or microdialysis technique-dependent components.
Conclusions: A joint model simultaneously describing the pharmacokinetics of cefuroxime in synovial fluid of the knee, interstitial fluid of muscle tissue and plasma after single intravenous infusion in patients undergoing elective knee arthroscopy was successfully developed. Overall, cefuroxime displayed good penetration abilities from the peripheral compartment into both synovial fluid and interstitial fluid of muscle tissue. As next step, a covariate analysis will be performed to identify factors influencing the pharmacokinetics of cefuroxime. Ultimately, the joint model incorporating potential covariate effects can be used to perform Monte-Carlo simulations to evaluate the probability of target attainment of the current dosing regimen for different pharmacokinetic/pharmacodynamic targets in the various matrices.
References:
[1] R. Schwameis, S. Syré, D. Marhofer, A. Appelt, D. Burau, K. Sarahrudi, C. Kloft, M. Zeitlinger. Pharmacokinetics of Cefuroxime in Synovial Fluid. Antimicrob. Agents Chemother., 61: e00992-17 (2017).
Reference: PAGE 27 (2018) Abstr 8668 [www.page-meeting.org/?abstract=8668]
Poster: Drug/Disease Modelling - Infection