DDMODEL00000311: Translational PKPD of isoniazid from zebrafish to humans

  public model
Short description:
Quantification of isoniazid internal exposure - response relationship in zebrafish larvae infected with Mycobacterium marinum as disease model for tuberculosis.
Original code
  • Anti-tuberculosis effect of isoniazid scales accurately from zebrafish to humans
  • Rob C van Wijk, Wanbin Hu, Sharka M Dijkema, Dirk-Jan van den Berg, Jeremy Liu, Rida Bahi, Fons J Verbeek, Ulrika S H Simonsson, Herman P Spaink, Piet H van der Graaf, Elke H J Krekels
  • British Journal of Pharmacology, 8/2020
  • Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Division of Animal Sciences and Health, Institute of Biology Leiden, Leiden University, Leiden, The Netherlands.
  • Background and purpose There is a strong need for innovation in anti?tuberculosis drug development. The zebrafish larva is an attractive disease model in tuberculosis research. To translate pharmacological findings to higher vertebrates, including humans, the internal exposure of drugs needs to be quantified and linked to observed response. Experimental approach In zebrafish studies, drugs are commonly dissolved in the external water, posing a challenge to quantify internal exposure. We developed experimental methods to quantify internal exposure, including nano?scale blood sampling, and to quantify the bacterial burden, using automated fluorescence imaging analysis, with isoniazid as paradigm compound. We used pharmacokinetic?pharmacodynamic modelling to quantify the exposure?response relationship responsible for the antibiotic response. To translate isoniazid response to humans, the quantitative exposure?response relationship in zebrafish was linked to simulated concentration?time profiles in humans, and two quantitative translational factors on sensitivity to isoniazid and stage of infection were included. Key results Blood concentration was only 20% of the external drug concentration. The bacterial burden increased exponentially and an isoniazid dose corresponding to 15 mg·L?1internal concentration (minimum inhibitory concentration) lead to bacteriostasis of the mycobacterial infection in the zebrafish. The concentration?effect relationship was quantified, and based on that relationship and the translational factors, the isoniazid response was translated to humans, which correlated well with observed data. Conclusions and implications This proof?of?concept confirms the potential of the zebrafish larvae as tuberculosis disease model in translational pharmacology, and contributes to innovative anti?tuberculosis drug development which is strongly needed.
Rob Christiaan van Wijk
Context of model development: Mechanistic Understanding;
Long technical model description: Zebrafish embryos are infected after 28 hours post fertilization with 200 CFU Mycobacterium marinum (strain E11), and after two days to establish infection are treated with increasing doses of isoniazid (0.25x - 10x MIC, MIC = 15 mg/L). Internal exposure is quantified in homogenates and blood samples. Bacterial burden is quantified by fluorescence imaging and automated image analysis. Final pharmacokinetic-pharmacodynamic model is a one-compartment model with age as covariate on absorption, and a linear exposure-response relationship on exponential growth of bacterial burden.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: The zebrafish larva infected with Mycobacterium marinum is used as disease model for tuberculosis and in anti-tuberculosis drug development. For the first time, an exposure-response relationships of isoniazid is quantified in this promising vertebrate.;
Modelling task in scope: estimation;
Nature of research: Fundamental/Basic research;
Therapeutic/disease area: Immunology;
Annotations are correct.
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  • Model owner: Rob Christiaan van Wijk
  • Submitted: Sep 4, 2020 8:49:50 AM
  • Last Modified: Sep 4, 2020 8:49:50 AM
  • Version: 13 public model Download this version
    • Submitted on: Sep 4, 2020 8:49:50 AM
    • Submitted by: Rob Christiaan van Wijk
    • With comment: Edited model metadata online.