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 were also performed to address differences in pyronaridine exposures among these populations and to explore the exposures of pyronaridine among recommended dosage regimens for pediatric and adult malaria patients. Healthy adults had a higher exposure to pyronaridine as compared to adult malaria patients. For the pediatric population, younger children had a higher exposure to pyronaridine as compared to older children. The overall range of pyronaridine exposures among dosing groups for adult and pediatric malaria patients were relatively similar. The cut-off values of pyronaridine pharmacokinetic parameters associated with successful treatment outcome were also determined by means of receiver operating characteristic (ROC) curve. These cut-off values can be used to optimize the outcome of malaria treatment. Additionally, Cox proportional hazard model was conducted to determine the relationship between several covariates and time to the occurrence of re-infection or recrudescence. The models showed that as the levels of predicted pyronaridine concentrations on day 7 increased, the risks of acquiring re-infection or recrudescence decreased. Finally, pharmacokinetic drug-drug interaction of pyronaridine and ritonavir was assessed based on the overlap pathway for metabolism of both drugs and the high rates of HIV and malaria co-infection. There was an effect of ritonavir on pyronaridine pharmacokinetics. However, the results were not considered clinically relevant. An increase in ritonavir exposure was observed in the presence of fixed dose PA.

A novel pyronaridine-artesunate (PA) combination is being developed as a 3:1 fixed ratio oral combination against P. falciparum and P. vivax malaria. Pyronaridine (PYR) has been used on a limited basis as monotherapy to treat malaria in some provinces in China since 1970, and there are minimal published data on pharmacokinetics of PYR in humans. In this thesis, the population pharmacokinetics (PPKs) of PYR is studied in different populations. In Chapter II, we develop a PPKs model in 91 healthy subjects participating in a Phase I study of PA. In addition, data from two Phase II and four Phase III studies of PA are pooled, and PPKs of PYR in 321 adult and 319 pediatric patients are investigated separately in Chapter III and IV, respectively. Chapter V provides comparisons of the results from each population. PYR pharmacokinetics in each population is best described by a two-compartment model with first order absorption and elimination from the central compartment. Although the same structural model is used, pharmacokinetics of PYR differs among the three populations. PYR is absorbed faster and more variably in patients. The weight-normalized total apparent volumes of distribution (V/F) in adult and pediatric patients are approximately 5 and 3 times larger than in healthy subjects. Adult and pediatric patients have a mean weight-normalized oral clearance (CL/F) approximately 2 times higher than healthy subjects but the drug is eliminated more slowly in patient populations due to a much larger V/F. The average elimination half-lives are 8, 11 and 18 days in healthy, pediatric and adult patient populations, respectively. Pharmacokinetic modeling suggests that lean body weight is an important predictor of apparent central volume (V2/F) in adult patients while actual body weight is a significant covariate of V2/F and CL/F in children. The parameters obtained from PPK modeling are plausible and estimated with acceptable precision. The final models are evaluated using a nonparametric bootstrap technique and visual predictive check. The final models are robust and adequately capture the overall pyronaridine pharmacokinetics. Further study in a broader patient population will be necessary to examine other covariates that influence pyronaridine pharmacokinetics.