Abstract
This thesis highlights the increasing importance and value of model-informed drug development (MIDD). MIDD enhances the efficiency of drug development by reducing time and capital cost through application of pharmacometrics techniques. Development of Oral Docetaxel plus Encequidar (oDox+E) at an early phase was used as the motivating example to demonstrate the value of MIDD. A GO / NO-GO framework based on the central question “Does a feasible regimen of oDox+E exist?” was answered using pharmacometrics techniques.
The output of each chapter formed pre-requisites to address the central question. In Chapter 2 a Phase I clinical human trial collected pharmacokinetic (PK) samples and demonstrated preliminary safety. In Chapter 3 a sensitive unbound drug assay was developed to allow direct PK comparison of IV docetaxel and oDox+E. In Chapter 4 optimal design was applied to obtain the most informative subset of PK samples for unbound analysis (given resource constraints). In Chapter 5 a fit for purpose, extrinsically validated population pharmacokinetic model was developed for IV docetaxel and oDox+E. Finally, in Chapter 6 simulations were performed which showed oDox+E as a multi-dose regimen could achieve comparable PK exposure to standard of care IV docetaxel. Thus, a feasible regimen of oDox+E was found to exist, and a Conditional Go decision was made.
The implementation of MIDD to answer the central question allowed 1) additional knowledge to be gained about the safety and effectiveness of oDox+E to inform the next phase of development, 2) the utility of MIDD to be highlighted (especially in the context of oncology drug development), and 3) present a case study for drug development entities to explore and implement MIDD. Drug development entities that strategically implement low-cost GO / NO-GO decisions facilitated by MIDD could capture significant efficiency gains across an entire portfolio of drugs. Efficient resource utilisation will lead to improved patient outcomes via expedited access to novel therapies.