Accelerating drug development in infectious diseases using zebrafish disease models supported by pharmacokinetic pharmacodynamic modeling as new approach methodology (NAM)

A zebrafish embryo/larva NAM workflow quantified bedaquiline PKPD, yielding an EC50 of 26.5 g/mL and Emax of 1.09–1.37 for delayed bacterial growth.

• Why it matters: Infectious-disease therapeutics need faster, more predictive in vivo screening than in vitro alone, while reducing mammalian experiments and avoiding misleading efficacy calls.
• What they did: The workflow selected compounds with tolerated doses above minimum inhibitory concentration, measured fluorescence efficacy at baseline and 24/48h, assessed internal exposure in homogenates and medium from 0–48h, then fit PKPD with non-linear mixed effects modelling.
• The result: For bedaquiline, the PKPD model linked exposure to delayed bacterial growth and supported translation to higher vertebrates, while clarithromycin showed negligible internal exposure after waterborne dosing, flagging false-negative risk.

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