In Vitro ADME Services

Platform Introduction

The absorption, distribution, metabolism, and excretion (ADME) properties of a drug represent the drug's disposition process by the body. ADME properties of a drug are determined by its structure. Measuring the ADME properties of a drug can provide an essential value for predicting its bioavailability and biological activity (i.e., whether a drug can reach its target and exhibit the corresponding therapeutic effect). In the 1990s, approximately 40-50% of drug candidates’ failure rate was attributed to unacceptable ADME properties in drug development ^[1]. Therefore, in recent years, the R&D team has introduced ADME assessment at the early stage of drug discovery and development to exclude undesirable compounds early and quickly at a low cost and focused resources on promising compounds for subsequent development.

The failure caused by ADME properties of the drug decreased to 10% in the year 2000. This achievement has been key to the development of in vitro ADME research.In the early years, the primary approach to predicting human in vivo PK performance was from in vivo pharmacokinetics (PK) data. Later, with the development of new synthetic strategies, the number of compounds for screening the ADME properties increased substantially. The study of their ADME properties also needed to be more extensive. In vitro, ADME experiments emerged. Since the 1990s, the variety and availability of human-derived reagents have increased for in vitro drug metabolism studies, making in vitro ADME research more convenient ^[2]. In addition to providing high-throughput screening at a low cost, in vitro ADME studies can also eliminate many factors and investigate a single ADME property. Human PK performance is more accurately predicted by combining the data obtained from in vitro studies with in vivo experiments.

The desirable ADME properties vary considerably based on the disease target, the delivery route, frequency of administration, the pharmacokinetic-pharmacodynamic (PK-PD) relationship, and market competition strategies. These factors make it impossible to design a common strategy for all projects. Typically, in the Lead Finding (LF) stage, the solubility, lipophilicity, permeability, and microsomal stability of compounds are determined first. The obtained data are used to build the structure-property relationship of compounds, screen chemical structure categories, and confirm the priority of multiple structural backbones. At the Lead Optimization (LO) and Pre-Clinical Candidate (PCC) stages, comprehensive in vitro ADME studies are usually required. These include multi-species metabolic stability, plasma protein binding, transporters related to drug interaction, and inhibition of the drug-metabolizing enzymes combined with animal PK data to predict human PK performance. In the Investigational New Drug (IND) stage, a comprehensive evaluation of in vitro ADME properties is required and conducted per the requirements of drug registration authorities. It should be noted that the preliminary in vitro ADME study is usually not designed for regulatory submission, so the results are typically not submitted as application materials but can be submitted as supplementary materials ^[3].