The study of pharmacokinetics in a clinical environment

Graduation date: 2010This dissertation presents a research series demonstrating the use of pharmacokinetic modeling and simulations as tools to assess drug concentration and disposition in patient populations. For drugs requiring therapeutic drug monitoring, these tools are necessary to ensure patients are receiving a safe and effective dose of medication to address their medical condition.\ud The second chapter describes a prospective study to validate pharmacokinetic modeling simulation aimed at determining optimal inter and intradialytic dosing of vancomycin for hemodialysis patients. Fifty percent of the patients with evaluable data maintained trough concentrations within the therapeutic range (15-20mg/L). The remaining fifty percent of the patients required individualization of dosing to produce troughs in the therapeutic range. Given this, it is advisable to use a weight-based dosing regimen as a start for patient treatment. Therapeutic drug monitoring and individualization should be implemented as well to ensure therapeutic drug concentrations.\ud The third chapter involves noncompartmental analysis of aprepitant plasma concentrations in an antiemetic regimen for patients undergoing hematopoietic stem cell transplantation. This study regimen has a first dose of 125mg on day 1, and 80mg daily until 4 days after the hematopoietic stem cell transplant. In spite of drug interactions from concomitant drug therapy, therapeutic concentrations of aprepitant were maintained. The study regimen can be applied in patients undergoing hematopoietic stem cell transplantation.\ud The fourth chapter examines the unique characteristics of vancomycin pharmacokinetics in patients with Acute Myelogenous Leukemia. (AML) Demographics and vancomycin drug concentration versus time data were gathered from a retrospective cohort. One-compartment pharmacokinetic equations with population pharmacokinetic parameters were used to predict drug concentrations. These were compared with measured concentrations. A shortened half-life and increased clearance for vancomycin was found in AML patients compared to a general population. Because of this, the vancomycin dose in a 24 hour period should be doubled relative to the general population.\ud The fifth chapter evaluates The University of Southern California Lab of Applied Pharmacokinetics MM-USC*PACK population modeling software using multiple model Bayesian pharmacokinetics for dosing vancomycin in AML patients. Of interest is the ability of the software’s included vancomycin population PK database to fit assayed drug concentrations of AML patients given the vancomycin dosing regimen. The root mean squared prediction error was not greater than 5.25 mg/L, given multiple options for estimation of creatinine clearance as a covariate in the modeling. Using the MM-\ud USC*PACK software with a population model developed from the cohort being evaluated should yield the best predictive performance and be a feasible dosing tool for patient care. Evaluation of pharmacokinetics of clinically available data as applied to improving drug dosing in patients is a consistent and common objective of the research in this thesis