CPSA Digest 2001

Proceedings -Thursday, October 11, 2001

ThOB1

Pre-Clinical Lead Optimization and Candidate Selection: Developability Perspective

Background
Traditional drug discovery and development functions focused on small molecules having ligand specificity and selectivity. Once a candidate was identified, it was handed over to Development to improve delivery issues. During this lead selection and optimization process, discovery and development scientists had little interaction. Thus, development times were long and costly due to the sequential nature of development.

Drugs fail to reach the marketplace or slow down in development for a variety of reasons. Some of these stopping points include poor biopharmaceutical properties (solubility, stability, permeability, metabolism, oral bioavailability), poor efficacy, toxicity or adverse effects, complexity of synthetic scale-up, and changes in the marketplace. The discovery process has changed out of necessity to one of much greater interaction between disciplines, higher throughput, and reduced timelines. The key focus of this discovery shift is to improve the probability of success for a drug candidate (quality more important than numbers), and thus eliminate the bad ones early in the process.

Premise
The goal of the discovery process should be to decide early on whether or not a compound is developable, and to increase the chance of success. Some of the questions raised during drug discovery include:

• Will the compound be bioavailable after oral administration?
• What is the anticipated dose?
• Can we find a formulation to compensate for such a low solubility?
• What determines the success of a formulation?
• Is it true that only crystalline material can be developed?
• What biopharmaceutics properties help in deciding whether a compound is developable?

Activity + Developability = Product Success

There are some determinations that can be made in silico, early in the lead selection stage. Some of these include:

• Solubility, log P, pKa
• Permeability; potential for metabolism
• Predictive toxicology
• Strategic decisions about preferred chemotypes

Developability assessments during the discovery process are made at the in vitro stage (lead selection), in vivo stage (lead optimization) and at the candidate selection stage. Some important assessments at each of these stages are listed below.

In Vitro Stage (Lead selection)

• Aqueous solubility
• Potential for chemical instability
• Prodrug potential?
• Caco-2/PAMPA permeability
• Protein binding
• CYP inhibition
• Metabolic stability
• Hepatotoxicity or other cellular toxicity

In Vivo Stage (Lead optimization)

• Aqueous solubility (vs pH), pKa, chemical stability, log P, non-aqueous solubility
• Oral bioavailability, clearance, elimination half-life
• Metabolic pathways
• Pharmacology-based assays, mutagenicity, teratogenicity
• Core process chemistry, potential synthetic difficulties

Candidate selection

• Crystallinity, hygroscopicity, salt evaluation, solid-state stability, pH-stability, delivery attributes, formulation potential
• Oral bioavailability and ADME in multiple species, dose and formulation dependence
• In vivo toxicology
• Purity, preliminary cost-of-goods
• Assay development, impurity profiling, degradation pathways
• Aggregation and precipitation potential

An analysis of MAD (Maximal Absorbable Dose) should be performed on drugs to assess their developability. Also, using the BCS (Biopharmaceutics Classification System established by the FDA) can help guide the early assessment of new compounds and clinical dosage form design strategies. These developability criteria need to be built-in to the drug discovery process to increase the odds of successful product commercialization.

Related Information

S. Venkatesh and R.A. Lipper, "Role of the Development Scientist in Compound Lead Selection and Optimization", Journal of Pharmaceutical Sciences, 89(2): 145-54, February 2000.

R.T. Borchardt, et al., (Eds), "Integration of Pharmaceutical Discovery and Development: Case Histories", Plenum Press: New York, 1998.

Return to Proceedings »