AN EVALUATION OF THE INTEGRATION OF PHARMACOKINETIC AND PHARMACODYNAMIC PRINCIPLES IN CLINICAL DRUG DEVELOPMENT - EXPERIENCE WITHIN HOFFMANN-LA-ROCHE

The integration of pharmacokinetic and pharmacodynamic principles into drug development has been proposed as a way of making it more rationa l and efficient. The use of these principles in drug development to ma ke scientific and strategic decisions is defined as the 'pharmacokinet ic-pharmacodynamic guided approach to drug development'. The objective s of this survey were: (i) to assess the extent the pharmacokinetic-ph armacodynamic guided approach to drug development has been used in a l arge multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug de velopment; and (iii) to identify factors which prevented the full appl ication of the pharmacokinetic-pharmacodynamic guided approach. This w as done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interv iewing the responsible clinical pharmacologist using a standardised qu estionnaire. (i) Benefits from using the pharmacokinetic-pharmacodynam ic guided approach were reported in every project, independent of deve lopment phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical stu dies was found to be the most important application of pharmacokinetic -pharmacodynamic results in terms of an impact on drug development. (i i) Time savings, up to several months, could be quantified in 8 projec ts during the entry-into-man studies and in 6 projects during the phas e II or III studies. In 4 projects, 1 clinical study was avoided. (iii ) The most important scientific factor preventing the full application of the approach was the lack of knowledge on the predictive value of the pharmacodynamic or surrogate marker for effect (6 projects). The r esults of the survey have shown that the use of the pharmacokinetic-ph armacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply t he pharmacokinetic-pharmacodynamic approach should be identified in ea ch project and a project specific strategy for the pharmacokinetic-pha rmacodynamic guided approach should be defined during phase 0 of drug development.