Accelerating drug development in infectious diseases using zebrafish disease models supported by pharmacokinetic-pharmacodynamic modeling as new approach methodology (NAM)
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract The development of novel therapeutics for infectious diseases remains a global health priority. To accelerate the treatment development, innovative strategies through new approach methodology (NAM) are needed to bridge speed of in vitro with predictive power of in vivo studies, while reducing mammalian experiments. The zebrafish ( Danio rerio ), particularly the embryo/larva, has been established as a valuable non-mammalian in vivo model in biomedical research. We developed a standardized and streamlined workflow for the zebrafish as NAM, which consisted of 3 steps: drug selection and efficacy evaluation, internal exposure assessment, and PKPD modelling. Compounds with higher tolerated doses than minimum inhibitory concentration were selected. Drug efficacy was quantified through longitudinal individual fluorescence microscopy at baseline and 24 and 48h on treatment. Drug exposure was quantified in larval homogenates and exposure medium from 0-48h on treatment. The PKPD relationship was quantified by non-linear mixed effects modelling. For case study bedaquiline, PKPD was quantified using a one-compartment model with age-depending elimination, and an Emax concentration-response relationship on the delayed logistic bacterial growth function, with an EC50 of 26.6 µg/mL and an Emax of 1.07-1.37. In the case of clarithromycin, in contrast, negligible internal exposure after waterborne treatment were observed, illustrating the risk of false negatives without internal exposure assessments. Bactericidal efficacy was confirmed by intravenous drug injections, showing a clear dose dependent antimycobacterial effect. The standardized zebrafish NAM workflow presented here facilitates the translation of drug efficacy to higher vertebrates, reducing rodent studies to confirmatory or replacing them completely, thus accelerating drug development.
Authors 13
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Affiliation as printed
Animal Sciences, Institute for Biology Leiden, Leiden University, Leiden, the Netherlands
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Bart van Lieshout Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
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Affiliation as printed
Animal Sciences, Institute for Biology Leiden, Leiden University, Leiden, the Netherlands
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Affiliation as printed
Infectious Diseases, Janssen Research & Development, Janssen Pharmaceutica NV. Beerse, Belgium
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Affiliation as printed
PSTS, Janssen Research & Development, Janssen Pharmaceutica NV. Beerse, Belgium
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Affiliation as printed
Infectious Diseases, Janssen Research & Development, Janssen Pharmaceutica NV. Beerse, Belgium
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Affiliation as printed
DMPK, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium
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Janssen (Belgium) · Maastricht University
Affiliation as printed
Maastricht MultiModal Molecular Imaging Institute (M4i), Maastricht University, Maastricht, Netherlands
PSTS, Janssen Research & Development, Janssen Pharmaceutica NV. Beerse, Belgium
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Affiliation as printed
Infectious Diseases, Janssen Research & Development, Janssen Pharmaceutica NV. Beerse, Belgium
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Elke H. J. Krekels Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Certara Inc, Radnor, PA, USA
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
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J G Coen van Hasselt Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
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Affiliation as printed
Animal Sciences, Institute for Biology Leiden, Leiden University, Leiden, the Netherlands
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Rob Christiaan van Wijk Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
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