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Applied Adaptive Optimal Design and Novel Optimization Algorithms for Practical Use
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

The costs of developing new pharmaceuticals have increased dramatically during the past decades. Contributing to these increased expenses are the increasingly extensive and more complex clinical trials required to generate sufficient evidence regarding the safety and efficacy of the drugs.  It is therefore of great importance to improve the effectiveness of the clinical phases by increasing the information gained throughout the process so the correct decision may be made as early as possible.   Optimal Design (OD) methodology using the Fisher Information Matrix (FIM) based on Nonlinear Mixed Effect Models (NLMEM) has been proven to serve as a useful tool for making more informed decisions throughout the clinical investigation. The calculation of the FIM for NLMEM does however lack an analytic solution and is commonly approximated by linearization of the NLMEM. Furthermore, two structural assumptions of the FIM is available; a full FIM and a block-diagonal FIM which assumes that the fixed effects are independent of the random effects in the NLMEM. Once the FIM has been derived, it can be transformed into a scalar optimality criterion for comparing designs. The optimality criterion may be considered local, if the criterion is based on singe point values of the parameters or global (robust), where the criterion is formed for a prior distribution of the parameters.  Regardless of design criterion, FIM approximation or structural assumption, the design will be based on the prior information regarding the model and parameters, and is thus sensitive to misspecification in the design stage.  Model based adaptive optimal design (MBAOD) has however been shown to be less sensitive to misspecification in the design stage.   The aim of this thesis is to further the understanding and practicality when performing standard and MBAOD. This is to be achieved by: (i) investigating how two common FIM approximations and the structural assumptions may affect the optimized design, (ii) reducing runtimes complex design optimization by implementing a low level parallelization of the FIM calculation, (iii) further develop and demonstrate a framework for performing MBAOD, (vi) and investigate the potential advantages of using a global optimality criterion in the already robust MBAOD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , p. 80
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 224
Keyword [en]
Nonlinear Mixed Effects Models, Pharmacometrics, Fisher Information Matrix, Approximation, Optimality Criterion, Parallelization, Model Based Adaptive Optimal Design
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-308452ISBN: 978-91-554-9766-8 (print)OAI: oai:DiVA.org:uu-308452DiVA, id: diva2:1049907
Public defence
2017-01-20, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-12-21 Created: 2016-11-26 Last updated: 2018-01-13
List of papers
1. PopED: An extended, parallelized, nonlinear mixed effects models optimal design tool
Open this publication in new window or tab >>PopED: An extended, parallelized, nonlinear mixed effects models optimal design tool
Show others...
2012 (English)In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 108, no 2, p. 789-805Article in journal (Refereed) Published
Abstract [en]

Several developments have facilitated the practical application and increased the general use of optimal design for nonlinear mixed effects models. These developments include new methodology for utilizing advanced pharmacometric models, faster optimization algorithms and user friendly software tools. In this paper we present the extension of theoptimal design software PopED, which incorporates many of these recent advances into aneasily useable enhanced GUI. Furthermore, we present new solutions to problems related to the design of experiments such as: faster and more robust FIM calculations and optimizations, optimizing over cost/utility functions and diagnostic tools and plots to evaluate designperformance. Examples for; (i) Group size optimization and efficiency translation, (ii) Cost/constraint optimization, (iii) Optimizations with different FIM approximations and (iv) optimization with parallel computing demonstrate the new features in PopED and underline the potential use of this tool when designing experiments. 

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-160475 (URN)10.1016/j.cmpb.2012.05.005 (DOI)000310828200030 ()
Available from: 2011-10-24 Created: 2011-10-24 Last updated: 2018-01-12
2. The effect of Fisher information matrix approximation methods in population optimal design calculations
Open this publication in new window or tab >>The effect of Fisher information matrix approximation methods in population optimal design calculations
2016 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 43, no 6, p. 609-619Article in journal (Refereed) Published
Abstract [en]

With the increasing popularity of optimal design in drug development it is important to understand how the approximations and implementations of the Fisher information matrix (FIM) affect the resulting optimal designs. The aim of this work was to investigate the impact on design performance when using two common approximations to the population model and the full or block-diagonal FIM implementations for optimization of sampling points. Sampling schedules for two example experiments based on population models were optimized using the FO and FOCE approximations and the full and block-diagonal FIM implementations. The number of support points was compared between the designs for each example experiment. The performance of these designs based on simulation/estimations was investigated by computing bias of the parameters as well as through the use of an empirical D-criterion confidence interval. Simulations were performed when the design was computed with the true parameter values as well as with misspecified parameter values. The FOCE approximation and the Full FIM implementation yielded designs with more support points and less clustering of sample points than designs optimized with the FO approximation and the block-diagonal implementation. The D-criterion confidence intervals showed no performance differences between the full and block diagonal FIM optimal designs when assuming true parameter values. However, the FO approximated block-reduced FIM designs had higher bias than the other designs. When assuming parameter misspecification in the design evaluation, the FO Full FIM optimal design was superior to the FO block-diagonal FIM design in both of the examples.

Keyword
Optimal design, Fisher information matrix, Full FIM, Block-diagonal FIM, FO, FOCE
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-306940 (URN)10.1007/s10928-016-9499-4 (DOI)000388634800005 ()27804003 (PubMedID)
Available from: 2016-11-07 Created: 2016-11-07 Last updated: 2018-01-13Bibliographically approved
3. Model based adaptive optimal design of a simulated adult to children bridging study using an FDA proposed precision criterion
Open this publication in new window or tab >>Model based adaptive optimal design of a simulated adult to children bridging study using an FDA proposed precision criterion
(English)Manuscript (preprint) (Other academic)
Keyword
Model Based Adaptive Optimal Design; Pediatric trial design; Sample Size estimation; Stopping criterion; NLMEM; Optimal Design
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-308434 (URN)
Available from: 2016-11-25 Created: 2016-11-25 Last updated: 2018-01-13
4. The effect of using a robust optimality criterion in model based adaptive optimization.
Open this publication in new window or tab >>The effect of using a robust optimality criterion in model based adaptive optimization.
2017 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 44, no 4, p. 317-324Article in journal (Refereed) Published
Abstract [en]

Optimizing designs using robust (global) optimality criteria has been shown to be a more flexible approach compared to using local optimality criteria. Additionally, model based adaptive optimal design (MBAOD) may be less sensitive to misspecification in the prior information available at the design stage. In this work, we investigate the influence of using a local (lnD) or a robust (ELD) optimality criterion for a MBAOD of a simulated dose optimization study, for rich and sparse sampling schedules. A stopping criterion for accurate effect prediction is constructed to determine the endpoint of the MBAOD by minimizing the expected uncertainty in the effect response of the typical individual. 50 iterations of the MBAODs were run using the MBAOD R-package, with the concentration from a one-compartment first-order absorption pharmacokinetic model driving the population effect response in a sigmoidal EMAX pharmacodynamics model. The initial cohort consisted of eight individuals in two groups and each additional cohort added two individuals receiving a dose optimized as a discrete covariate. The MBAOD designs using lnD and ELD optimality with misspecified initial model parameters were compared by evaluating the efficiency relative to an lnD-optimal design based on the true parameter values. For the explored example model, the MBAOD using ELD-optimal designs converged quicker to the theoretically optimal lnD-optimal design based on the true parameters for both sampling schedules. Thus, using a robust optimality criterion in MBAODs could reduce the number of adaptations required and improve the practicality of adaptive trials using optimal design.

Keyword
Optimal Design; Model Based Adaptive Optimal Design; Dose Optimization, Optimality Criteria, Robust Optimal Design
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-308433 (URN)10.1007/s10928-017-9521-5 (DOI)000405835000003 ()28386710 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2016-11-25 Created: 2016-11-25 Last updated: 2018-01-13Bibliographically approved

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