CPSA Digest 2001

Proceedings -Wednesday, October 10, 2001

WOE2

Strategies for Overcoming the Bottlenecks in Assessing the Toxicity in New Pharmaceuticals

Background

The drug development pathway begins with identification of a molecular target and ends, many years and millions of investment dollars later, in the clinic with human evaluations for safety and efficacy. As the strategies and models for drug development have changed over the years, the bottlenecks to progress have shifted from one aspect to another. Presently in 2001, the "more is better" approach is supported, where more and more compounds are synthesized, screened for activity and developed. However, screening more compounds does NOT guarantee finding a strong drug candidate out of that lot. Resource limitations with various human resources and funding constraints continue to provide controls on the process.

Premise

Three bottlenecks are presently identified in the discovery and evaluation of drug candidates:

1. Toxicology
   
2. ADME/PK
   
3. Physico-Chemical characteristics

In toxicology, bottlenecks include the length of time required to conduct studies, compound requirements, relevance of animal findings to humans, and identification of human target organ toxicities and biomarkers. In ADME/Pharmacokinetics, bottlenecks include the relevance of specific animal species to humans, absorption and bioavailability issues, non-optimal pharmacokinetics, and the inhibition and induction of drug metabolism. Bottlenecks in the area of physico-chemical characteristics include solubility and stability assessments.

When should Toxicology studies begin on a development compound? Note that most compounds fail prior to or during Phase I clinical studies, for various reasons including pharmacokinetics (8-33%), toxicity (20-29%) or pharmacology (31-45%). Some "anti-bottleneck" toxicity strategies include better lead optimization and selection of drug candidates, learning how to provide rapid answers with minimal drug, and improving the integration of Toxicology with Discovery and ADME/PK.

Some of the roles, divisions and discovery support areas in Toxicology research are shown below.

The "Investigative Toxicology" group can provide the following support roles in lead optimization and selection:

• Initial gene toxicity evaluation
• Support of single dose pharmacokinetics
• Identify and define target organ toxicities
• Determine target liabilities
• Support multiple dose toxicokinetic studies
• Evaluate potential in-license candidates

The use of specific predictive assays and model cell systems can also aid in reducing toxicology bottlenecks. For example, mitochondrial assays can be used to determine the effects on normal cell function in response to a toxic agent insult, such as effects on the following: DNA/RNA synthesis, protein synthesis, fatty acid oxidation, oxidative phosphorylation, ATP synthesis, permeability, apoptosis, and pH and ion regulation. The Affymetrix "rat toxicology chip" is another predictive technique, a powerful tool for detecting changes in gene expression.

Value

Overall, the role of Toxicology in drug development and drug safety evaluation is an important one and Toxicology is an integral component of the entire in the drug development process. There is much more to be learned and put into implementation with regard to faster and more predictive toxicity assays to aid in smarter lead optimization and selection.

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