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Quantifying Variability in drug disposition, response and public health outcomes: The implementation of pharmacometric based modeling and simulation approaches

Jin, Yuyan (2011) Quantifying Variability in drug disposition, response and public health outcomes: The implementation of pharmacometric based modeling and simulation approaches. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The aim of the dissertation was to identify the systematic contributors that modify the estimated population parameters and that explain sources of variability in drug exposure (Chapter 2-4), response, and clinical outcome (Chapter 5-7). The source of measurable variability evaluated in the thesis include patient characteristics in chapter 2-3, patient behavior in chapter 4 (e.g. dosing history), biological system in chapter 5-7, and inferior clinical practice in chapter 5-7. The dissertation was predominantly non-linear mixed effect modeling and Monte Carlo simulation methods in NONMEM® and R. Our results in chapter 2-4 showed that incorporating covariate information into population PK models identified substantial systematic contributors to the variability in drug exposure for both perphenazine and escitalopram. Race and smoking status in the past week were identified as two significant covariates affecting clearance of perphenazine. CYP 2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. The measurement error associated with an incorrect or incomplete dosing history affected the population PK parameter estimation of escitalopram in the non-linear mixed effect modeling process. Furthermore, our simulation results in chapter 5-7 showed that three intervention approaches may lead to lower cardiovascular risk compared to current clinical practice strategy: 1) BP can be calibrated with respect to clinic visit times with consideration of PK/PD/dosing regimen. 2) BP-misclassification in current clinical practice is around 20~45% depends on clinic visit time. Optimal clinic visit time exists. In general, patients should avoid early morning and late afternoon visit which lead to the highest BP misclassification. 3) It is important to decrease patients' BP in a timely fashion. Initiating antihypertensive treatment with the higher tolerable dose as well as setting a lower goal BP of 120 mm Hg resulted in a significantly lower cardiovascular risk. In conclusion, the dissertation identified three potential interventions to be considered in the clinical practice or antihypertensive drug labeling for better BP management: BP calibration based on clinic visit time; patients should generally have post treatment clinic visit times between 11:00 AM ~ 3:00 PM; a high dose strategy for antihypertensive drug therapy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVollmer, Regis Rvollm@pitt.eduVOLLM
Committee MemberBies,
Date: 11 January 2011
Date Type: Completion
Defense Date: 4 October 2010
Approval Date: 11 January 2011
Submission Date: 11 January 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Clinical Practice; Hypertension; NONMEM; Pharmacometrics
Other ID:, etd-01112011-114551
Date Deposited: 10 Nov 2011 19:31
Last Modified: 15 Nov 2016 13:36


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