A fixed-dose combination of
pyronaridine and
artesunate, one of the
artemisinin-based combination
therapies, has been used as a potent
antimalarial treatment regimen. Recently, several studies have reported the
antiviral effects of both drugs against severe acute respiratory syndrome coronavirus two (SARS-CoV-2). However, there are limited data on the pharmacokinetics (PKs), lung, and trachea exposures that could be correlated with the
antiviral effects of
pyronaridine and
artesunate. The purpose of this study was to evaluate the pharmacokinetics, lung, and trachea distribution of
pyronaridine, artesunate, and
dihydroartemisinin (an active metabolite of
artesunate) using a minimal physiologically-based pharmacokinetic (PBPK) model. The major target tissues for evaluating dose metrics are blood, lung, and trachea, and the nontarget tissues were lumped together into the rest of the body. The predictive performance of the minimal PBPK model was evaluated using visual inspection between observations and model predictions, (average) fold error, and sensitivity analysis. The developed PBPK models were applied for the multiple-dosing simulation of daily oral
pyronaridine and
artesunate. A steady state was reached about three to four days after the first dosing of
pyronaridine and an accumulation ratio was calculated to be 1.8. However, the accumulation ratio of
artesunate and
dihydroartemisinin could not be calculated since the steady state of both compounds was not achieved by daily multiple dosing. The elimination half-life of
pyronaridine and
artesunate was estimated to be 19.8 and 0.4 h, respectively.
Pyronaridine was extensively distributed to the lung and trachea with the lung-to-blood and trachea-to-blood concentration ratios (=Cavg,tissue/Cavg,blood) of 25.83 and 12.41 at the steady state, respectively. Also, the lung-to-blood and trachea-to-blood AUC ratios for
artesunate (
dihydroartemisinin) were calculated to be 3.34 (1.51) and 0.34 (0.15). The results of this study could provide a scientific basis for interpreting the dose-exposure-response relationship of
pyronaridine and
artesunate for
COVID-19 drug repurposing.