Anti-tuberculosis effect of isoniazid scales accurately from zebrafish to humans.

Background And Purpose: There is a clear 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 usually dissolved in the external water, posing a challenge to quantify internal exposure. We developed experimental methods to quantify internal exposure, including nanoscale blood sampling, and to quantify the bacterial burden, using automated fluorescence imaging analysis, with isoniazid as the test compound. We used pharmacokinetic-pharmacodynamic modelling to quantify the exposure-response relationship responsible for the antibiotic response. To translate isoniazid response to humans, quantitative exposure-response relationships in zebrafish were 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 internal concentration (minimum inhibitory concentration) leads 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 study confirmed the potential of zebrafish larvae as tuberculosis disease models in translational pharmacology and contributes to innovative anti-tuberculosis drug development, which is very clearly needed.