ROLE OF PHARMACOKINETIC-PHARMACODYNAMIC PRINCIPLES IN RATIONAL AND COST-EFFECTIVE DRUG DEVELOPMENT

An important goal of drug development is to define dose and concentrat ion-response relationships for new drugs and biologics. Such critical information from controlled clinical trials can provide primary eviden ce of efficacy and safety and an informative database for devising dos ing instructions for clinical use. This article describes applications of pharmacologic principles [pharmacokinetic-pharmacodynamic (PK-PD)] and modeling methods for drugs in which the evaluation process is gui ded by and/or identifies significant PK and/or PD variability in drug response. In the case of the recently registered immunosuppressive age nt, tacrolimus, preclinical PK-PD in model systems can be used to rati onally design safe and effective immunomodulatory dosing regimens for phase 1 clinical studies. Furthermore, a study design based on concent ration control guided by a novel artificial intelligence modeling syst em (AIMS) can be efficiently applied to conduct randomized clinical tr ials in autoimmunity and to implement cost-effective therapeutic drug monitoring of tacrolimus and cyclosporine in clinical transplantation. In the case of a cardioselective beta-adrenergic blocking agent, beta xolol, marketed for essential hypertension, population PD modeling can be shown to be a more efficient method for estimating dose response c ompared with standard statistical tests. Using a sigmoid E(max) PD mod el, only a fraction (40 of 300) of the randomized patients was needed to demonstrate dose response. Therefore, two methods, i.e., PD modelin g of dose response and AIMS-guided dosing, can achieve significant cos t benefits for drug developers, patient care, and the health care syst em.