Application of Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung and Trachea Exposure of Pyronaridine and Artesunate in Hamsters

Abstract

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 (=C_avg,tissue/C_avg,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.

Keywords: COVID-19; artesunate; drug repurposing; minimal physiologically-based pharmacokinetic (PBPK) model; pyronaridine.

Figure 1

Structure of the minimal PBPK model for (a) pyronaridine, (b) artesunate, and dihydroartemisinin in hamsters. (c) The perfusion rate-limited kinetics was used to describe the equilibrium between blood and tissue concentrations.

Figure 2

Pharmacokinetic profiles for (a) low-dose (180 mg/kg) and (b) high-dose (360 mg/kg) groups of pyronaridine in hamsters. Blue squares, green triangles, and red circles with solid lines represent lung, trachea, and blood concentrations of pyronaridine, respectively.

Figure 3

Blood concentrations for artesunate and dihydroartemisinin after multiple dosing of (a) low-dose (60 mg/kg) and (b) high-dose (120 mg/kg) artesunate to hamsters. Closed circles and open squares are blood concentrations of artesunate and dihydroartemisinin, respectively.

Figure 4

Normalized sensitivity coefficients for the minimal PBPK models of pyronaridine and artesunate. (a) pyronaridine; (b) artesunate; (c) dihydroartemisinin.

Figure 5

Comparison of the observed and predicted PK parameters. (a) C_max; (b) AUC_Day1; (c) AUC_Day3. The dashed lines represent 2-fold errors between the observations and predictions.

Figure 6

Simulated PK profiles for daily oral dosing of pyronaridine with (a) low-dose (180 mg/kg) and (b) high-dose (360 mg/kg) for 14 days. Blue, green, and red solid lines are simulated profiles for lung, trachea, and blood, respectively. Blue squares, green triangles, and red dots represent observed concentrations for lung, trachea, and blood, respectively.

Figure 7

Simulated PK profiles for daily oral dosing of artesunate with low- and high-dose for 3 days. Blue, green, and red solid lines are simulated profiles for lung, trachea, and blood, respectively. Circles and squares are observed concentrations of artesunate and dihydroartemisinin, respectively. Blood concentrations of artesunate in low-dose (a) and high-dose (b) group; blood concentrations of dihydroartemisinin in low-dose (c) and high-dose (d) group; lung concentrations of artesunate in low-dose (e) and high-dose (f) group; lung concentrations of dihydroartemisinin in low-dose (g) and high-dose (h) group; trachea concentrations of artesunate in low-dose (i) and high-dose (j) group; trachea concentrations of dihydroartemisinin in low-dose (k) and high-dose (l) group.