Population pharmacokinetics and pharmacodynamics of pyronaridine

ii To my dad, my mom, and my sister. For their unconditional love, care, support, and encouragement. iii It is not the fruits of scientific research that elevate man and enrich his nature, but the urge to understand, the intellectual work, creative or receptive. Albert Einstein Ideas and Opinions, 1954 iv ACKNOWLEDGMENTS This thesis would not have been possible without the help and support of all the wonderful people in my life, to only some of whom it is possible to give particular mention here. Above all, I would like to thank my advisor Professor Larry Fleckenstein for his guidance, mentoring, and encouragement throughout my Ph.D. program. Without his devotion and mentorship, I would never have accomplished this big part of my life. who have provided ideas and helpful advices. I would also like to thank all my former and current colleagues: Dr. Thitima Wattanavijitkul and Dr. Denise Morris for your advice, encouragement and support. Carrie Morris, thank you for all your help and suggestions. Amal Suleiman Ayyoub, thank you for your great friendship. thank you for being good friends and sharing all moments together. thank you for being good lab colleagues. My Thai friends in Iowa City and in Thailand: thank you for their generosity, moral support, and friendship. Finally, I would like to thank my father, Thammanoon Methaneethorn, my mother, Phensri Methaneethorn, thank you so much for your unconditional love, and support. Words cannot express my appreciation. I would not have come this far without you. I also want to thank my sister, Jutima Methaneethorn, thank you for all your supports and advice in all aspects. v ABSTRACT Pyronaridine/Artesunate (PA) 3:1 fixed dose combination is a novel artemisinin-based combination therapy (ACT) in development for the treatment of acute uncomplicated Plasmodium falciparum or Plasmodium vivax malaria. An understanding of both pharmacokinetics and pharmacodynamics of pyronaridine is of importance in order to achieve optimal therapeutic outcome. In this thesis, population pharmacokinetic models for pyronaridine in healthy subjects, and adult and pediatric malaria patients were developed. Pyronaridine pharmacokinetics in both adult and pediatric populations were best described by a two compartment model with first order absorption and elimination from the central compartment. A presence of malaria infection and body weight were the significant covariates that explained pyronaridine pharmacokinetic variability in the adult population. For the pediatric population, age was the only significant covariate that explained pyronaridine pharmacokinetic variability. Monte Carlo simulations …