Pharmacokinetics of Novel Antidiabetic Agents and a Highly Effective Antimalarial Trioxane (99-411)

Abstract

Drug research is a unique multi-disciplinary process heading towards the development of therapeutic agents in the area of currently unmet medical needs. The drug research can be divided functionally into discovery and development process [1]. The discovery and development process of therapeutically useful drugs requires an enormous amount of money and time due to high attrition rates of new chemical entities (NCEs)/drug candidate. Lack of efficacy and toxicity are considered to be major reasons for drug failures and pharmacokinetics (PK) governs them to large extent [2]. According to recent literature, it is estimated that only one in ten of the agents that enter clinical development are successful, with an average cost of US $ 500-800 million and a typical time scale of 10-15 years from preclinical discovery research to regulatory approvals [3]. Pharmacokinetics is the study of the time course of absorption, distribution, metabolism and elimination (ADME) of the drugs in biological system and helps to understand the relationship between pharmacological and toxicological effects and concentration of a drug and its metabolites in the body fluid. The systematic application of PK can therefore considerably reduce the cost and time involved in new drug development [4]. Today PK and metabolism are among the most highly interactive disciplines in the pharmaceutical research and development and intimately involve in the design of new chemical entities [5-7]. Fundamentally, ADME/PK information is critical in all phases of a fully integrated drug development program.The goal of ADME-guided synthesis is to maximize the ability of NCEs to access the therapeutic target. Once a lead compound is identified, it is subjected to preclinical PK/ADME studies. Preclinical pharmacokinetics broadly divided into three areas: (i) PK at the discovery levels that enables selection of lead chemical, (ii) toxicokinetics, or PK during toxicology studies, and (iii) preclinical studies in animals that support the clinical studies and regulatory obligations. Historically, an inappropriate pharmacokinetic property has been a major reason for the failure of compounds in the later stage of development. This is supported by an analysis of cause of failure of drugs selected for development. It has been reported that inappropriate kinetics in humans accounted for 39 % of the failures.