2025 DMDG | 51st Open Meeting: Shaping the future of DMPK

This study aimed to explore concentration-dependent safety limits and evaluate the risk of combined solvent use via intravenous administration of Solutol HS 15 in Beagle dogs. Additionally, we assessed tolerability differences across species, including mini-pigs, cynomolgus monkeys, and Dutch belted rabbits, to inform species-appropriate formulation design.

In this study, the culture conditions for plated monkey hepatocytes were optimised by adjusting cell density and evaluating different lots of hepatocytes from multiple vendors. After optimising conditions, the expected metabolism profile for our model compound, siRNA01, a commercially available GalNAc-conjugated siRNA, was obtained. Furthermore, comparative metabolite profiling of siRNA01 in optimised plated monkey hepatocytes and monkey liver homogenate revealed highly similar profiles.

The discovery and development of oral drug candidates during the preclinical stage require a thorough understanding of how various segments of the gastrointestinal (GI) tract influence absorption. Both small molecule compounds and biologics face significant challenges, such as poor solubility, chemical and enzymatic degradation, variable permeability, first-pass metabolism, efflux mechanisms, immunogenicity, and stability issues. Traditional animal models, including single-segment perfusion in rodents, are limited by their inability to compare across intestinal segments and the non-reusability of animals.

Peptides, as targeted therapeutics for metabolic disorders and cancer, have profoundly reshaped our modern pharmaceutical industry. Understanding the pharmacokinetic behaviour and pharmacological/toxicological effects of these drugs critically depends on determining the unbound fraction (fu) in plasma. However, inherent challenges such as stability and non-specific binding issues make obtaining reliable fu values particularly difficult for peptides using traditional plasma protein binding (PPB) experiments, such as equilibrium dialysis, ultracentrifugation, or ultrafiltration. To address these issues, this study developed a biomimetic chromatography method to evaluate human plasma protein binding.