Katie Lynch (1), Ming Sun (1), Theis Mariager (2, 3), Jacob Bodilsen (2, 3), Martijn Manson (1), Lisebeth de Lange (1), Tingjie Guo (1).
(1) Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. (2) Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark. (3) Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Introduction: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, with mortality ranging between 20 – 70% [1]. For effective treatment of TBM, antibiotics must achieve adequate concentrations within the central nervous system (CNS). Therefore, understanding CNS pharmacokinetics and pharmacodynamics (PK/PD) is critical for the rational dosing of anti-tuberculous drugs. However, the PK/PD of moxifloxacin is poorly understood, and CNS PK studies in humans are limited and challenging for ethical reasons. Objective: The aim of this study was to systematically understand CNS pharmacokinetics in pigs through the use of physiologically based pharmacokinetic (PBPK) modelling, ultimately providing a framework for translation to humans. Method: A CNS semi-physiologically based pharmacokinetic model, based on robust brain physiology, was developed using a middle-out approach. In vivo porcine data from the plasma, cortical brain extracellular fluid, and ventricular, cisternal and lumbar cerebrospinal fluid of healthy female pigs was integrated into the model [2], as well as literature-derived physiological parameters. The structural model was developed based on previously published brain models [3] and refined by utilizing pig-specific CNS physiology, and drug-specific properties of moxifloxacin. The developed model was then translated to humans by substituting human CNS physiological parameters in the place of pig parameters. Human CNS physiological parameters were identified from the literature or, when unobtainable, estimated using interspecies scaling methods. Results: The pig model accurately predicted moxifloxacin’s PK profile in plasma and CNS compartments. The PBPK model predicted greater influx of moxifloxacin between the plasma and brain than efflux. This finding aligns with the area under the concentration-time curve (AUC) ratio of tissue free drug to plasma free drug (ƒAUCtissue/ƒAUC plasma (unbound)) which exceeded 1 in all evaluated pig brain compartments [2]. However, the ƒAUCtissue/ƒAUC plasma (unbound) measured in study pigs contrasts with current understanding of moxifloxacin transport in the human CNS, where this ratio is thought to be less than 1 in healthy individuals [4]. Therefore, it is possible that there are species differences in the active transport of moxifloxacin. Additionally, applying a combination of interspecies scaling methods to translate pig PK parameters best predicted healthy human moxifloxacin PK profiles in plasma and subarachnoid space after a 400mg dose. The scaling of CNS barrier-related parameters was best described using the ratio between human and pig brain volumes with an exponent of 0.67 [5]. CSF flow-related parameters were most effectively scaled using the brain volume ratio with an exponent of 0.95 [6]. Conclusion: The developed translational CNS PBPK modelling approach provides a new, physiologically accurate computational tool for predicting moxifloxacin concentrations in pigs and humans. Overall, it provides a foundation for future studies on patient CNS PK, which could in turn be used to explore potentially effective dosing regimens for moxifloxacin in TBM. References: [1] Cresswell, F. V. et al. Intensified antibiotic treatment of tuberculosis meningitis. Expert Review of Clinical Pharmacology vol. 12 267–288 (2019). [2] Mariager, T. et al. Continuous evaluation of single-dose moxifloxacin concentrations in brain extracellular fluid, cerebrospinal fluid, and plasma: a novel porcine model. Journal of Antimicrobial Chemotherapy vol. 79 1313-1319 (2024) [3] Westerhout, J. et al. Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats. AAPS Journal vol. 14, 543–553 (2012). [4] Kanellakopoulou, K. et al. Pharmacokinetics of moxifloxacin in non-inflamed cerebrospinal fluid of humans: Implication for a bactericidal effect. Journal of Antimicrobial Chemotherapy vol. 61, 1328–1331 (2008). [5] Kawai, R. et al. Physiologically Based Pharmacokinetic Study on a Cyclosporin Derivative, SDZ IMM 125. Journal of Pharmacokinetics and Biopharmaceutics vol. 22, 327 – 365 (1994). [6] Seymour, R. et al. Scaling of cerebral blood perfusion in primates and marsupials. Journal of Experimental Biology vol. 218, 2631–2640 (2015).
Reference: PAGE 33 (2025) Abstr 11553 [www.page-meeting.org/?abstract=11553]
Poster: Drug/Disease Modelling - CNS