Document Type


Date of Degree

Fall 2016

Access Restrictions

Access restricted until 01/31/2020

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Fleckenstein, Lawrence

First Committee Member

Salem, Aliasger

Second Committee Member

Donovan, Maureen

Third Committee Member

Murry, Daryl

Fourth Committee Member

Oleson, Jacob


Pyronaridine/Artesunate (PA) 3:1 fixed dose combination is a novel artemisinin based combination therapy (ACT) for the treatment of acute uncomplicated Plasmodium falciparum or Plasmodium vivax malaria. There are limited published data on the pharmacokinetics of pyronaridine in humans, an area of importance to achieve optimal therapeutic outcome.

Chapter 1 of this thesis contains a general review of malaria and pyronaridine basic pharmacokinetic properties. In Chapters 2 and 3, population pharmacokinetic models of pyronaridine in healthy and malaria-infected adult subjects as well as pediatric malaria patients are presented. Pyronaridine pharmacokinetics were best described by a two compartment model with first order absorption and elimination from the central compartment. Covariates of malaria infection, body weight, and age significantly explained pyronaridine pharmacokinetic variability in the adult population; whereas in the pediatric population model, an allometric scaling approach was utilized to incorporate the effect of body weight, age and formulation were retained as significant covariates. Chapter 2 addresses the differences in the pharmacokinetic parameters between healthy subjects and malaria-infected patients, and the lack of such differences between healthy Korean and Caucasian subjects as well as between malaria-infected Asian and African patients. In addition, Chapter 3 places particular focus on describing any formulation-specific effects associated with the granule formulation, in order to confirm the weight-based dosing of Pyramax® granules.

Chapter 4 assessed the relative bioavailability of pyronaridine of the tablet and granule formulations and revealed a lack of any clinically relevant formulation-related difference in pyronaridine exposure with the geometric mean ratios and 90% confidence intervals for pyronaridine primary and secondary outcomes of interest being fully within the no relevant difference range of 80 – 125%.

Finally, in Chapter 5, Generalized Estimating Equations (GEE) and logistic regression models were used to investigate the statistical association of the likelihood of liver enzyme elevations with pyronaridine pharmacokinetic parameter values in healthy and malaria-infected adult subjects. It aimed at investigating the higher observed likelihood of liver enzyme elevations in healthy subjects and addressed the shortcomings which may have influenced the significance of the results.


xv, 130 pages


Includes bibliographical references (pages 127-130).


Copyright © 2016 Amal Ayyoub

Available for download on Friday, January 31, 2020