Case Study 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.