Beyond CL and V: A comprehensive approach to human pharmacokinetic predictions.

This article presents a comprehensive examination of processes related to the prediction of human pharmacokinetics (PK), a crucial task of clinical drug candidate selection. By systematically incorporating in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo PK data with expert judgement, the study achieves high-quality human PK predictions for 40 orally administered compounds from Boehringer Ingelheim's new chemical entity (NCE) portfolio. Overall, the article provides a detailed evaluation of and guidance for a structured process to predict full concentration-time profiles beyond single-parameter predictions, using state-of-the-art methodologies.

Multi-Task ADME/PK prediction at industrial scale: leveraging large and diverse experimental datasets.

ADME (Absorption, Distribution, Metabolism, Excretion) properties are key parameters to judge whether a drug candidate exhibits a desired pharmacokinetic (PK) profile. In this study, we tested multi-task machine learning (ML) models to predict ADME and animal PK endpoints trained on in-house data generated at Boehringer Ingelheim. Models were evaluated both at the design stage of a compound (i.

Towards holistic Compound Quality Scores: Extending ligand efficiency indices with compound pharmacokinetic characteristics.

The suitability of small molecules as oral drugs is often assessed by simple physicochemical rules, the application of ligand efficiency scores or by composite scores based on physicochemical compound properties. These rules and scores are empirical and typically lack mechanistic background, such as information on pharmacokinetics (PK). We introduce new types of Compound Quality Scores (CQS, specifically called dose scores and c scores), which explicitly include predicted or, when available, experimental PK parameters and combine these with on-target potency.

A novel mitochondrial complex I ROS inhibitor partially improves muscle regeneration in adult but not old mice.

It is unclear whether mitochondrial dysfunction and redox stress contribute to impaired age-related muscle regenerative capacity. Here we characterized a novel compound, BI4500, that inhibits the release of reactive oxygen species (ROS) from the quinone site in mitochondrial complex I (site I). We tested the hypothesis that ROS release from site I contributes to impaired regenerative capacity in aging muscle.