An Integrated Framework for Evaluating Poor Biorelevant Stability during First-in-Human (FIH) Development

Poor biorelevant stability can complicate oral drug development, but its relevance depends on systemic exposure to degradation products and their associated safety risks. pH-dependent degradants represent physiology-driven transformation products that do not align with conventional definitions of impurities or metabolites, complicating their evaluation during development. This work presents an integrated, exposure-based risk assessment framework to evaluate their clinical relevance.

Compound A degradation was evaluated under biorelevant conditions, gastric pH (pentagastrin)-modified rat and dog pharmacokinetic studies, mechanistic absorption modeling, pharmacological evaluation, and mutagenicity assessment.

Compound A exhibited rapid acid-mediated degradation in fasted-state simulated gastric fluid (~ 50% loss within 1 h), resulting in three pH-dependent degradants. In vivo studies demonstrated low and variable systemic degradant exposure. The degradants exhibited no meaningful pharmacological activity and were assessed as having low mutagenic risk. Mechanistic absorption modeling incorporating pH-dependent degradation kinetics indicated that degradant formation was solubility-limited. Because individual degradant ADME properties were unknown, conservative assumptions were applied and predicted total systemic degradant exposure remained below the 10% threshold referenced in Metabolites in Safety Testing (MIST) guidance. Despite uncertainty in degradant stability, degradants were detectable and incorporated into a clinical monitoring strategy.

This work integrates biorelevant stability, in vivo pH-modified pharmacokinetics, absorption modeling, pharmacology, and safety assessment within an exposure-based risk framework, supporting progression of an acid-labile compound into first-in-human clinical trials without premature formulation modification or extensive qualification studies.