Case Studies
Preclinical Development
Preclinical Assessment of Metabolite Contribution to Drug’s Mode of Action
Benefits of Case:
• Simplified development plan featuring conventional pharm/tox package
• Greater focus in bioanalytical method development and validation program
• More targeted and cost-contained formulation program
• Significant reduction (40%) in preclinical development costs by reducing the number of GLP bioanalytical test samples required to support the regulatory filing.
Background and Challenge:
The Client wished to reformulate a reference-listed drug and use in a new indication. However, the drug’s primary pharmacologic effects were highly species specific and failed to correlate with drug plasma levels, suggesting the contribution of an unknown metabolite to the drug’s mode of action. The Client wanted a new formulation to deliver therapeutic benefit while limiting exposure to a known active metabolite that had been previously correlated with limiting adverse effects.
PharmaDirections Strategy:
• Assemble an expert team to evaluate existing PK/PD and drug metabolism data and generate a development strategy
• Identify laboratories capable of conducting metabolite identification studies in parallel with sophisticated compound-specific pharmacology assays to determine beneficial and adverse activities of the metabolites identified
• Translate findings into a bioanalytical development plan that would support formulation development and clinical proof of concept
The Objectives:
PharmaDirections’ team of preclinical experts conducted a critical assessment of the available PK/PD, drug metabolism and safety data and identified gaps as well as new information about the pharmacology and pharmacokinetics of the drug and its known metabolites. Metabolic stability studies were conducted and putative metabolites identified. In parallel, to maintain timelines, in vivo assays were developed based on an understanding of the mechanisms presumed to underlie the drug’s therapeutic and adverse effect profiles in order to provide quick read-outs of pharmacologic activity. PharmaDirections rapidly determined the pharmacologic profiles obtained in vivo were not consistent with low levels of an unknown metabolite, and instead focused the bioanalytical program on measuring parent drug plasma levels and one major metabolite in a tandem GLP assay.
Value for the Client:
• Clinical assessment of the ‘adverse effect’ metabolite was done cost-effectively in a modified bioanalytical assay that measured both parent and metabolite, saving the Client over $200,000 in development charges.
• The Client did not have to pursue unnecessary preclinical studies but could remain focused on the essential components of the program, reducing the timeline to initial clinical studies by 3 months and saving the Client $100,000.
• Formulation efforts focused on measuring parent drug levels of the drug candidate to predict efficacy
• PharmaDirections staff worked with the Client to take several new formulations into a Phase 1 study to confirm preclinical expectations for the PK/PD relationship of parent (efficacy) and metabolite (adverse effects) in humans, fulfilling a gap in their technical capability.
Download PDF version of this case study>
Candidate Selection and Lead Optimization
Benefits of Case:
• Generated a preclinical research plan designed to demonstrate the pipeline potential of the Client’s core drug discovery platform
• Identified the critical path for candidate screening and rapid preclinical proof of concept
• Established pharmacological, safety and chemical criteria for lead candidate selection
Background and Challenge:
A company was in the early stages of constructing a pipeline of proprietary leads using a novel chemistry platform with the ability to transform the absorption and tissue uptake of known drugs. PharmaDirections was tasked with designing a preclinical research strategy that could demonstrate the full potential of the platform in building a pipeline of targeted lead molecules, while accelerating the identification of potential development candidates.
PharmaDirections Strategy:
• Assemble an expert team to evaluate the key benefits of the Client’s core technology platform and highlight the critical success factors for lead generation
• Define those in vitro and in vivo studies most likely to generate useful data in demonstrating the robustness of the platform in delivering compounds of potential interest
• Establish objective criteria for lead candidate selection based on industry standard benchmarks for potency, selectivity, bioavailability, safety, physical properties and ‘drugability’
• Recommend ways of collecting and presenting comprehensive data sets to optimize interest by potential partners and investors
The Objectives:
PharmaDirections assembled an expert team with both general preclinical development and therapeutic area specific experience to review the technology and the data collected by the Client to date. PharmaDirections performed a gap analysis on the existing data and the Client’s current research plan to identify critical data needs and potential program pitfalls. These activities resulted in a cost- and time effective research strategy designed to highlight the principle strengths of the core technology platform in generating leads of interest while advancing the most attractive candidates rapidly through development. By setting criteria for the ‘drugability’ of the chemical leads as well as basic requirements for efficacy, safety and bioavailability in animal models, PharmaDirections was able to focus the Client on those compounds with the greatest potential for successful IND track development.
Value for the Client:
The Client was able to increase focus on critical path studies while avoiding the collection of data considered non-strategic to company and program goals. The proposed research plan resulted in convincing preclinical proof of concept while realizing time and cost savings by anticipating investor/partner questions and anticipating issues in downstream IND enabling activities.
Download PDF version of this case study>
|
