News from Europe's pharmaceutical manufacturing industry coupled with upcoming events, and exclusive articles and interviews from industry experts. WEEKLY
Zebrafish: a multifaceted approach for drug safety assessment
Using mammalian species as preclinical models for safety pharmacologies can be expensive, time consuming and require large amounts of compound. Zebrafish larvae have been shown to be predictive for human pharmacology and are both transparent and small enough to fit into a 96-well plate reducing compound usage as well as increasing throughput of screening. Hence, in vivo screening for potential liabilities can be applied at a much earlier stage of the drug discovery process than has previously been..
Many compounds fail in preclinical development because of safety-related problems, but identifying 'predictable' safety or
toxicity liabilities earlier in the process could lead to improved design and selection of compounds that are more likely
to be approved. It is estimated that a 10% improvement in predicting failure before the initiation of clinical trials could
save $100 million (€68.4 million) in development costs per drug.1 One area where this can be applied is in preclinical in vivo models, which are currently limited to rodents, dogs and monkeys. These models, although effective, are costly and use large
amounts of compounds, often precluding early detection of liabilities associated with the compounds.
Figure 1: An adult zebrafish. Scalebar = 0.89cm
A model gaining increasing recognition from the pharmaceutical industry is the zebrafish, which offers a novel approach to
toxicity and safety screening. This approach is both cost effective and high throughput.
What are zebrafish?
Figure 2: A zebrafish larva at 3 dpf. Organs such as the heart are clearly visible because of the optical clarity of the larvae
at this age. Scalebar = 0.24mm
Zebrafish (Danio rerio; Figure 1) is a small freshwater fish originating from the rivers of northern India. The zebrafish model system possesses
numerous advantages for medium- to high-throughput screening of compounds, such as the relative ease of maintaining large
stocks of fish, its high fecundity and its rapid embryonic development ex utero, whereby all the major organs are represented at 3 days post-fertilization (dpf), facilitating experimental manipulation.
As the larvae are transparent, it allows direct in vivo observation of tissue by noninvasive methods (Figure 2).2 Furthermore, the organization of the zebrafish genome and the genetic pathways controlling signal transduction and development
are highly conserved between zebrafish and man.3 At 7 dpf, the larvae are approximately 4 mm long. Because of this small size, assays can be undertaken in 96-well plates
and, as the larvae can live in as little as 200 μL of fluid, only a few milligrams of compound are required for screening
(Figure 3). Thus, in vivo analysis of the effects of compounds can be undertaken much earlier in the drug discovery process than has previously been
possible, which is facilitated by the fact that zebrafish are dimethylsulphoxide (DMSO) tolerant up to 1% v/v and readily
absorb compounds from the water. The high fecundity of zebrafish and the relative ease of maintaining large stocks also provide
investigators with ample numbers of larvae to analyse in high-throughput screens compared with conventional in vivo models. These properties have established zebrafish as excellent model systems.4
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