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 rational and efficient. The use of these principles in drug development to make scientific and strategic decisions is defined as the 'pharmacokinetic-pharmacodynamic guided approach to drug development'. The objectives of this survey were: (i) to assess the extent the pharmacokinetic-pharmacodynamic guided approach to drug development has been used in a large multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug development; and (iii) to identify factors which prevented the full application of the pharmacokinetic-pharmacodynamic guided approach. This was done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interviewing the responsible clinical pharmacologist using a standardised questionnaire. (i) Benefits from using the pharmacokinetic-pharmacodynamic guided approach were reported in every project, independent of development phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical studies was found to be the most important application of pharmacokinetic-pharmacodynamic results in terms of an impact on drug development. (ii) Time savings, up to several months, could be quantified in 8 projects during the entry-into-man studies and in 6 projects during the phase 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 results of the survey have shown that the use of the pharmacokinetic-pharmacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply the pharmacokinetic-pharmacodynamic approach should be identified in each project and a project specific strategy for the pharmacokinetic-pharmacodynamic guided approach should be defined during phase 0 of drug development.