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 . 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 . 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 .
In recent years, our in vitro ADME team has made progress in many ways. First, a variety of advanced automated liquid workstations and LC-MS/MS analysis technologies have been incorporated into in vitro ADME studies to improve further the assays' speed, quality, and throughput. Secondly, the in vitro assay portfolio of ADME studies has continued to expand, especially in the fields of drug-transporter interactions, drug metabolism studies of non-cytochrome P450 enzymes, in vitro ADME studies of peptide drugs, and protein binding studies of covalent inhibitors. The screen methods and experimental methodologies are relatively mature for traditional small molecule drugs, and our team has acquired vast experience and strategies in this area. More new modalities with complex structures have emerged from the recent R&D pipelines, including Proteolysis-Targeting Chimeras (PROTACs), oligonucleotides, and antibody-conjugated drugs (ADC). There are many challenges in the in vitro ADME study of these new modalities. We continuously expand the tools to support the ADME studies of these new modalities.
Screen chemical structure classes to provide 1 – 3 lead compounds with a reasonably diverse structural series.
Evaluate and improve the drug properties of lead compounds and help to obtain preclinical drug candidates with the best drug-like properties.
As required by new drug registration authorities, perform preclinical ADME evaluation. These parameters play an essential role in the species and dose selection of initial toxicity studies and complement the toxicokinetic data.
We have teams focused on in vitro ADME experiments and analysis, respectively, with first-class experimental, analytical capabilities and project throughput to ensure rapid and high-quality data delivery.
The standard assays are validated with commercial drugs. The results are highly consistent with the literature data.
The assays are highly reproducible, with control compounds undergoing thousands of experiments. The existing assays are regularly validated using commercial drugs every year.
When setting up a new assay, multi-dimensional investigations are performed to ensure the reliability of experimental data.
High-throughput and comprehensive service typesWe can provide various services from screening to IND application, with more than 100 assays and one-stop service to the clients. Automation can ensure continuous improvement of throughput.
Fast data delivery
High-quality dataThe application of automation can reduce human error and improve data quality. A complete set of in vitro ADME evaluation services can be provided to meet the submission requirements from FDA, EMA, and NMPA for new drugs. At present, the IND applications of hundreds of drug candidates have been completed, and all of them have passed the on-site audit by the regulatory authority.
Experienced researchersMore than 70% of employees have a master’s degree. The core team has more than 15 years of ADME research experience, providing valuable data in a short time to save resources and accelerate the development progress.