Modeling and simulation applications with potential impact in drug development and patient care

• Main Author: Li, Claire
• Other Authors: Bies, Robert R.
• Language: en_US
• Published: 2015
• Subjects: modeling and simulation; pharmacokinetics; pharmacodynamics; genetics; Molecular pharmacology > Research > Evaluation > Methodology; Drug development > Pharmacokinetics; Drug development > Molecular genetics; Drugs > Physiological effect > Mathematical models; Simulation methods > Research > Evaluation > Methodology; Mathematical models > Research > Evaluation > Methodology; Drugs > Metabolism; Drugs > Design; Clinical trials > Research > Evaluation; Drugs > Testing; Drugs > Toxicology; Patient-centered health care; Pharmacokinetics > Research
• Online Access: http://hdl.handle.net/1805/5969

Indiana University-Purdue University Indianapolis (IUPUI) === Model-based drug development has become an essential element to potentially make drug development more productive by assessing the data using mathematical and statistical approaches to construct and utilize models to increase the understanding of the drug and disease. The modeling and simulation approach not only quantifies the exposure-response relationship, and the level of variability, but also identifies the potential contributors to the variability. I hypothesized that the modeling and simulation approach can: 1) leverage our understanding of pharmacokinetic-pharmacodynamic (PK-PD) relationship from pre-clinical system to human; 2) quantitatively capture the drug impact on patients; 3) evaluate clinical trial designs; and 4) identify potential contributors to drug toxicity and efficacy. The major findings for these studies included: 1) a translational PK modeling approach that predicted clozapine and norclozapine central nervous system exposures in humans relating these exposures to receptor binding kinetics at multiple receptors; 2) a population pharmacokinetic analysis of a study of sertraline in depressed elderly patients with Alzheimer’s disease that identified site specific differences in drug exposure contributing to the overall variability in sertraline exposure; 3) the utility of a longitudinal tumor dynamic model developed by the Food and Drug Administration for predicting survival in non-small cell lung cancer patients, including an exploration of the limitations of this approach; 4) a Monte Carlo clinical trial simulation approach that was used to evaluate a pre-defined oncology trial with a sparse drug concentration sampling schedule with the aim to quantify how well individual drug exposures, random variability, and the food effects of abiraterone and nilotinib were determined under these conditions; 5) a time to event analysis that facilitated the identification of candidate genes including polymorphisms associated with vincristine-induced neuropathy from several association analyses in childhood acute lymphoblastic leukemia (ALL) patients; and 6) a LASSO penalized regression model that predicted vincristine-induced neuropathy and relapse in ALL patients and provided the basis for a risk assessment of the population. Overall, results from this dissertation provide an improved understanding of treatment effect in patients with an assessment of PK/PD combined and with a risk evaluation of drug toxicity and efficacy.