Integration of physicochemical and pharmacokinetic parameters in lead optimization: a physiological pharmacokinetic model based approach.
There have been major strides in the development of novel ways of investigating drug like properties of new chemical entities (NCE) in the last three decades. Identification of ideal properties of a clinical candidate that would give a clinical proof of concept (POC) is the most critical step in the discovery process. Besides the biological dose-response relationship, the pharmacokinetic parameters play the most vital role in influencing the therapeutic response or toxicity of NCE. While there are numerous techniques to understand various drug-like properties individually, the behavior of an NCE in a dynamic in vivo system which influences its therapeutic or toxic effects is a composite function of its various physicochemical and pharmacokinetic parameters. This implies the need to understand the collective influence of various measured parameters, and knowing how variations made in them can result in favorable pharmacodynamic or toxicokinetic properties. Understanding this behavior holds the key to a successful and time efficient lead optimization process. Physiological based pharmacokinetic models (PBPK) are of great interest in this context as they involve a natural way of integrating the individual compound property to physiological properties, providing a rational approach to predict drug like behavior (an ideal behavior identified may be addressed generally as Target Product Profile) in vivo. In the current review, various physiological pharmacokinetic models addressing absorption, tissue distribution and clearance are discussed along with their application in integrating various physicochemical and ADME parameters to predict human pharmacokinetics helping lead optimization.
Benjamin
Biju
B
Metabolism and Pharmacokinetics, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot- 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon, Haryana, India. bijub_2000@yahoo.com
Barman
Tarani Kanta
TK
Chaira
Tridib
T
Paliwal
Jyoti K
JK
D000042:Absorption / Q000502:physiology; D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D014018:Tissue Distribution
D004364:Pharmaceutical Preparations