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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.