Drug Discovery: Pharmacokinetic/Pharmacodynamic Fitting and Simulation

Abstract

As widely known, more than 40% of the past failure in drug development is solely

due to improper ADME properties of the new chemical entities (NCEs). The NCEs

recognized exert highest pharmacological action may not be the optimize NCEs for further

drug development. Based on convenience for the patients, the oral or any other extravascular

dosage form such as nasal, pulmonary, rectal etc. are the most desired formulations. The

extravasular dosing as a means for systemic treatment needs absorption process. Although the

NCEs can exert significant pharmacological actions but have very low bioavailabiliy (BA),

the pharmaceutical companies may discard these NCEs from their pipe lines. This leads to

the concept of “Drug-Likeness” screening. However, the limitation in bioavailability can be

the most important for the development of the oral formulations. Recently, the impact of

absorptive/secretive processes on a drug’s bioavailability has been recognized. Owe to the

discovery of significantly vast numbers of the transporters on the surface of the cells which

manage the uptake and efflux of NCEs and the possibility of integrate this knowledge with

basic mathematical model for fitting the data or simulations, pharmaceutical companies can

predict the biopharmaceutics and pharmacokinetics of NCEs more rapidly and precisely. The

current available in vitro and in vivo techniques in combination with new in silico will

significantly improve the drug discovery and development. Integration of the solid

knowledge from chemical structure to pharmacokinetic until the final pharmacodynamics

process which is the last objective for the benefits of the patients needs mechanistic

approaches. These mechanistic approaches will be illustrated in this article in order to

provide an overview and idea on what is available with regards to various experimental

model.