Defense Date

2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Jogarao Gobburu

Second Advisor

F. Douglas Boudinot

Abstract

Pharmacometrics is a quantitative science that is rapidly changing the landscape of drug development, and particularly so for the pediatric population. The motivation behind the research underlying this dissertation is to contribute towards the improvement of pediatric drug development by the astute application of pharmacometric methods. Two distinct research areas have been focused upon: 1- improving pediatric pharmacokinetic (PK) trial design and 2- improving pediatric dosing of warfarin by using a genetics-based dosing regimen. The first project examined in detail the feasibility of and simulation-based methodology for implementing a recent regulatory PK quality standard. The focus was on designing pediatric PK trials that employ sparse sampling and population analysis methods, using a simulation-estimation platform. The research provided clarity on the impact of various trial design elements, such as PK sampling, adult data inclusion, PK variability and analysis method on sample size adequacy to honor the standard. The PK quality standard was found to be practically feasible in terms of sample size adequacy. Informative sampling schedule for a given number of PK samples per subject is assumed during trial design. Recommendations are made to: 1- use prior adult or pediatric data for trial design and analysis, wherever possible and 2 - use one-stage population analysis methods and biologically feasible covariate models for designing pediatric PK studies. The second project involved derivation of the first ever pediatric warfarin dosing regimen, including starting dose and titration scheme, based on pharmacogenetics (Cyp2c9 *1/*2/*3 and VKORc1 -1629 G>A polymorphisms). While extensive research and several dosing models for warfarin use in adults exist, there is paucity of data in pediatrics. A validated adult warfarin population PKPD model was bridged using physiological principles and limited pediatric data to arrive at a pediatric PKPD model and dosing regimen. Pediatric data (n=26) from an observational study conducted at the Children’s Hospital Los Angeles (CHLA) was used to qualify the pediatric model. A 2-step pediatric starting dose based on body weight (<20 kg and ≥20 kg) for each of 18 (6 Cyp2c9 x 3 VKORC1) genotype categories is proposed. The titration scheme involves percentage changes relative to previous dose, based on latest patient INR. The dosing regimen targets a major (≥ 60%) proportion of INRs within therapeutic range of 2.0-3.0, by the second week into warfarin therapy. Simulataneously, bleeding and thromboembolic risks are minimized via minimal proportions (≤ 10% and ≤ 20%) of INRs > 3.5 and INRs < 2.0, respectively. In simulations, the proposed dosing regimen performed better on target INR outcomes than the standard-of-care dosing used in the CHLA patients. Given the challeneges in and low likelihood of conducting pediatric warfarin clinical studies, the proposed dosing regimen is believed to be an important advance in pediatric warfarin therapy. Prospective warfarin studies in pediatrics using the proposed dosing regimen are recommended to refine and validate the suggested dosing strategy.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2011

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