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Anti‐tuberculosis e...
Anti‐tuberculosis effect of isoniazid scales accurately from zebrafish to humans
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- Van Wijk, Rob C., 1991- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Leiden University, Leiden, The Netherlands
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- Hu, Wanbin (författare)
- Leiden University, Leiden, The Netherlands
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- Dijkema, Sharka M. (författare)
- Leiden University, Leiden, The Netherlands
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- Van den Berg, Dirk-Jan (författare)
- Leiden University, Leiden, The Netherlands
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- Liu, Jeremy (författare)
- Leiden University, Leiden, The Netherlands
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- Bahi, Rida (författare)
- Leiden University, Leiden, The Netherlands
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- Verbeek, Fons J. (författare)
- Leiden University, Leiden, The Netherlands
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- Simonsson, Ulrika S. H., Professor (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Spaink, Herman P. (författare)
- Leiden University, Leiden, The Netherlands
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- Van der Graaf, Piet H. (författare)
- Leiden University, Leiden, The Netherlands; Certara QSP, Canterbury, UK
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- Krekels, Elke H. J. (författare)
- Leiden University, Leiden, The Netherlands
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(creator_code:org_t)
- 2020-11-03
- 2020
- Engelska.
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 177:24, s. 5518-5533
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Abstract
Ämnesord
Stäng
- Background and purposeThere 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 approachIn 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 resultsBlood 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 implicationsThis 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- Translational pharmacology
- Pharmacokinetics
- Pharmacodynamics
- Tuberculosis
- Modelling
- Simulation
- Imaging
- In vivo
- Pharmacology
- Farmakologi
- Farmakokinetik och läkemedelsterapi
- Pharmacokinetics and Drug Therapy
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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Van Wijk, Rob C. ...
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Hu, Wanbin
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Dijkema, Sharka ...
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Van den Berg, Di ...
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Liu, Jeremy
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Bahi, Rida
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visa fler...
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Verbeek, Fons J.
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Simonsson, Ulrik ...
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Spaink, Herman P ...
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Van der Graaf, P ...
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Krekels, Elke H. ...
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visa färre...
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