A biopharmaceutical classification-based Right-First-Time formulation approach to reduce human pharmacokinetic variability and project cycle time from First-In-Human to clinical Proof-Of-Concept

A Right-First-Time approach is described for developing bona fide formulations for First-In-Human (FIH) to Proof-Of-Concept (POC) studies to meet an overarching goal of reduced project cycle time from IND to NDA (as short as four years). Bona fide formulations are tailor-made according to the drug's biopharmaceutical properties including solubility, permeability and stability. Solubilization techniques are used extensively to reduce oral absorption variability for most compounds. Bona fide formulations contain all necessary functional excipients such as diluent, solubilizer, stabilizer, pH adjuster, disintegrant and lubricant so formulation changes are minimized to avoid significant PK bridging studies. Cycle time of FIH formulation development is aligned with IND-enabling toxicology studies, generally 4-6 months. Resources range from 0.5 full time equivalents (FTE) for a BCS-1 compound to 3 FTE for a BCS-4 compound with high drug delivery hurdles. We have achieved our goal by taking the same formulation from FIH to POC 90% of the time and maintaining the same formulation platform from POC to commercial manufacturing 80% of the time in the past eight years. This strategy enables cycle time reduction from 7 to 4 years for IND to NDA by overlapping clinical study phases and eliminating clinical downtime due to PK bridging studies.