Application of In Silico, In Vitro and In Vivo ADMET/PK Platforms in Drug Discovery

Abstract

Drug discovery is a risky and expensive business fraught with high attrition rates. The health-care benefits and financial rewards that can be realised if successful have, however, ensured the relevance and continued growth of the pharmaceutical industry. The major reasons for high attrition rates during drug discovery include lack of efficacy, toxicity, inadequate pharmacokinetics (PK), and market forces, factors which can be complexly interrelated. PK has been shown to affect the efficacy and safety of new chemical entities (NCEs). The pharmaceutical industry responded by frontloading the characterisation of the processes that determine the PK of compounds, that is, absorption, distribution, metabolism and excretion (ADME). The ADME data are being used to guide medicinal chemists in the design of molecules with favourable disease-specific PK properties. In late stages of drug discovery, the preclinical ADME data are being used to predict human PK and safety of NCEs. As African research scientists initiate drug discovery activities, integration of PK, in the traditionally medicinal chemistry- and disease pharmacology-driven efforts, is important towards ensuring increased chances of discovering good candidate drugs (CD). We have therefore set up in silico, in vitro and in vivo ADMET platforms which various African drug discovery scientists can access. Drugs for non-communicable diseases fail more from lack of efficacy than poor PK and vice versa. Drug discovery efforts in Africa are also mainly based on natural products for which little is known or can be inferred from the PK of conventional synthetic drugs. These factors point to the need of promoting the sciences and technologies of PK research at many African institutions.