METHODOLOGICAL ISSUES IN PHARMACOKINETIC-PHARMACODYNAMIC MODELING

This article presents the theoretical and practical aspects involved i n the design and analysis of pharmacokinetic-pharmacodynamic modelling studies. The main features of the protocol of pharmacokinetic-pharmac odynamic studies are discussed with special focus on experimental desi gns in relation to individual and population approaches. Some basic ph armacodynamic models (such as linear, log-linear, hyperbolic and sigmo id models) are presented as well as more complex time-dependent models (effect compartment and physiological indirect response, tolerance mo dels) which are required when the concentration-effect relationship sh ows a hysteresis loop. The methods of estimation, with special focus o n the individual and populations approaches, are covered, along with t he way pharmacodynamic models and methods of estimation can be applied to real data and the information required to criticise the results of modelling. We also present some real problems frequently encountered when performing pharmacokinetic-pharmacodynamic modelling and give som e potential solutions (problems with hysteresis loops, lack of converg ence, problems with residuals). The last section discusses the signifi cance of pharmacodynamic parameters.