Lead candidate, pharmacokinetic evaluation

Successful completion of the above experiments will characterize methods for use in evaluating a lead candidate in animal models. If a candidate is selected for further development, the method will need to be validated (3,4) for each matrix and for each species before being used to support definitive toxicology, drug metabolism, and pharmacokinetic studies. 

Lead optimisation is the synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness (IUPAC). This phase begins with the first chemical lead or lead series selected for optimisation (i.e. the "lead series selected" milestone) and concludes with a decision for an optimized compound to enter preclinical development (i.e. the "pre-clinical candidate selected" milestone). This phase consists of testing of a compound to determine the chemical structure that has the optimum potency and selectivity for the target in question. The phase includes the search for backup compounds and may also include early ADME and toxicity evaluation. 

The principal issue in the drug discovery process is the high failure rate in the clinical trials, mainly due to liabilities related to poor pharmacokinetics (PK), poor efficacy, and high toxicity. The earlier lead optimization (LO) phase then represents a crucial step in the drug discovery process, since it involves the preparation and the selection of suitable drug candidates. In view of the increasing need for speed in the preclinical research and development, the determination of activity and selectivity is performed simultaneously with the evaluation of pharmacokinetic and toxicity properties. This multiparametric approach allows the early selection of the compounds with the best overall balanced druglike profile [1]. 

After optimization, scientists test the lead compounds in more sophisticated models including pharmacokinetics, pharmacodynamics, and toxicity. The optimal molecule selected from these assessments is then declared a new dmg candidate and moves on to the next phase (development). If a program is successful, it may take a total of 3-6 years from target selection and validation through lead generation, lead optimization, and preclinical evaluation in animals to candidate selection for a potential new medicine. 

The specificity of an assay evaluates the potential interferences from matrix components and from the different animal species to be used in pharmacology and toxicology experiments. Samples from each species to be studied are analyzed neat (with no added compound) and fortified with known amounts of the lead, and the results are calculated using a standard curve prepared in assay diluent. The responses obtained from the neat samples indicate the level of interference from each matrix, and the calculated amounts in the fortified samples show the difference in absolute recovery from the matrix compared with the candidate in buffer. If the absolute recovery is low, i.e., less than 50%, and/or highly variable, i.e., greater than 25%, the assay may not have the desired characteristics to quantify the lead in collected specimens. Additional development should be expended on such a method so that the assay will provide reliable results that can be used to evaluate the pharmacokinetic profile of the lead. 

---