Preclinical Studies

The preclinical testing stage of drug development focuses on obtaining critical safety and pharmacology data needed to take a drug to clinical testing in humans. The main goals of preclinical studies are to determine a drug's pharmacodynamics (PD), pharmacokinetics (PK), ADME, and toxicity.

Preclinical testing provides the greatest opportunity for improving the efficiency of bringing new drugs to market. Clinical trials are vastly more expensive than preclinical studies. Whenever a preclinical test can be used to prevent a clinical trial failure, the cost and risk of drug-discovery is reduced.

Advances in Preclinical Testing

Starting in the mid 1990s, rapid technological advances in in vitro preclinical testing dramatically changed the scope and value of preclinical studies. It became possible to test compounds in vitro against human cells, producing data that complement in vivo animal data by adding data predictive of human metabolism and toxicity.

This new technology produced a dramatic efficiency increase. In the early 1990s, 40% of clinical trial failures were due to ADME Tox reasons. Now that figure is 10% and falling. Apredica is at the forefront of implementing these technological advances in preclinical testing, which are continuing to evolve at a rapid pace.

Before these technological advances, the preclinical development phase was simpler and more linear than it is today, but also much less powerful. As recently as the late 1990s the preclinical stage involved just initial efficacy testing and GLP animal toxicity studies. Now the preclinical stage utilizes a powerful array of in vitro tests that can be performed at the pace of discovery -- in fast-paced, cost-effective, reproducible, robust, and predictive non-GLP processes. Results from these tests are fed back to the discovery team who incorporate these findings to guide their medicinal chemistry efforts.

The Role of ADME Tox in Preclinical Testing

Because the chances of any New Chemical Entity (NCE) ever becoming a marketable drug are so tiny, the role of a preclinical CRO is to help clients quickly and cost-effectively identify which compounds are unlikely to succeed in clinical trails. The sooner preclinical studies identify these high-risk candidates, the greater the resources available for discovering and developing compounds that will succeed.

Although a few of the in vitro screens definitively identify compounds that cannot succeed in clinical trials, in practice the in vitro data are principally about liability identification. These liabilities need to be considered in the context of efficacy data and therapeutic need. Liabilities that would be inconsequential for a cancer remedy could be entirely unacceptable for a cold remedy.

Many successful drugs have one or two ADME Tox liabilities, but none have several. Most drug discovery NCEs, however, have several ADME Tox liabilities. Preclinical testing identifies the compounds with large liabilities so that resources can be directed towards compounds with fewer liabilities.

Stages of Preclinical Testing

The enhanced scope, complexity, and importance of preclinical development now makes it as multi-staged as clinical development has been for decades, with its phases 1, 2, and 3 of increasing scales of human testing. Preclinical now also has three phases, which begin with fast, cost-effective, non-GLP, in vitro studies and end in more costly and time-consuming GLP in vivo studies.

Although the in vitro ADME Tox stage can be addressed through high-throughput preclinical screening, which has the on-paper advantage of lower costs per assay, unfortunately most NCEs will fail in preclinical ADME Tox screening. Consequently, it is most cost effective to avoid full batteries of preclinical tests on all compounds because the majority of them will fail on a battery of inexpensive tests.

As a preclinical CRO, Apredica's approach is to begin with the assays that are the most cost effective, as a function of their high failure rates and low costs. As compounds pass these preclinical tests, they move on to studies where the failure rates are lower, and costs higher. Thus, the in vitro phase of preclinical testing can be further broken down into four stages:

1. Physiochemical Properties: solubility, stability
2. In Vitro ADME Tox Screen: permeability, cell-based toxicity, cyp inhibition screen, microsomal stability
3. Detailed In Vitro Toxicity: ic50 cyp inhibition, hERG
4. Advanced Lead Characterization: cyp identification, metabolite profiling

Why Outsource to a Preclinical CRO?

For small drug-discovery firms, outsourcing ADME Tox to a preclinical CRO is the only economically viable route. For companies producing large numbers of NCEs, insourcing becomes an option. However, outsourcing to a preclinical CRO has many compelling advantages associated with increased expertise and lower total costs:

• Access to a team of drug-discovery experts with ADME Tox experience across a broad range of compound structures and therapeutic targets
• No setup costs for recruiting and equipment acquisition
• No delay associated with setting up an in-house department
• No wasted capacity or delays associated with uneven volumes of new compounds
• No shut down costs associated with finishing preclinical development

Why Choose Apredica as Your Preclinical ADME Tox CRO?

Apredica maximizes your speed and efficiency.

• Scientist-to-Scientist Communications
  Nothing is more frustrating to high-level scientists than to have to communicate through non-scientific sales and service personnel to get science done. That's why all accounts with Apredica are served by Ph.D.-level Study Managers.


• Fast Turnaround
  The direction taken by medicinal chemistry is substantially influenced by ADME Tox results. While your medicinal chemists are waiting for ADME Tox results, they could be wasting time following a dead-end lead. Apredica will provide ADME Tox assay results for you in just days. And for increased speed and convenience, if you're in the greater Boston area we'll even send a courier to pick up your samples.


• Service Focus
  Some preclinical CROs have their own drug-discovery programs that may distract them from servicing clients or even pose a risk to your intellectual property. The only drug-discovery programs Apredica advances are those of our clients.

If you'd like to learn more about how preclinical contract research can help your drug-discovery effort get to market faster and at lower cost, please contact our client services.