The pharmaceutical industry now recognises the importance of the newly defined discipline of pharmacometrics. Pharmacometrics uses mathematical models to describe and then predict the performance of new drugs in clinical development. To ensure these models are useful, the clinical studies need to be designed such that the data generated allows the model predictions to be sufficiently accurate and precise. The capability of the available software to reliably estimate the model parameters must also be well understood. This thesis investigated two important areas in pharmacometrics: optimal design and software estimation performance. The three optimal design papers progressed significant areas of optimal design research, especially relevant to phase II dose response designs. The use of exposure, rather than dose, was investigated within an optimal design framework. In addition to using both optimal design and clinical trial simulation, this work employed a wide range of metrics for assessing design performance, and was illustrative of how optimal designs for exposure response models may yield dose selections quite different to those based on standard dose response models. The investigation of the optimal designs for Poisson dose response models demonstrated a novel mathematical approach to the necessary matrix calculations for non-linear mixed effects models. Finally, the enormous potential of using optimal adaptive designs over fixed optimal designs was demonstrated. The results showed how the adaptive designs were robust to initial parameter misspecification, with the capability to "learn" the true dose response using the accruing subject data. The two estimation performance papers investigated the relative performance of a number of different algorithms and software programs for two complex pharmacometric models. In conclusion these papers, in combination, cover a wide spectrum of study designs for non-linear dose/exposure response models, covering: normal/non-normal data, fixed/mixed effect models, single/multiple design criteria metrics, optimal design/clinical trial simulation, and adaptive/fixed designs.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-182284 |
| Date | January 2012 |
| Creators | Maloney, Alan |
| Publisher | Uppsala universitet, Institutionen för farmaceutisk biovetenskap, Uppsala |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 166 |
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