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 (=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.

Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update

“…Exposure-response/toxicity relationships have been suggested for daunorubicin and daunorubicinol, but this still needs to be validated for defining target therapeutic ranges [183,184]. Physiologically based PK data suggest that epirubicin PK may be affected by hepatic and renal UGT2B7 gene expression, plasma albumin concentration, age, BSA, GFR, hematocrit and sex [185]. As with gemcitabine, pirarubicin may benefit from sparse sampling for reliable PK estimations making TDM certainly feasible once target concentrations will have been defined [186].…”

Docetaxel, Cyclophosphamide, and Epirubicin: Application of PBPK Modeling to Gain New Insights for Drug-Drug Interactions

“…In addition, in terms of drug elimination, they directly added the intrinsic clearance of the metabolic enzyme to the model, which somewhat ignored the nonlinearity of docetaxel. Besides, the previously developed docetaxel and epirubicin PBPK models were not built or evaluated for use in DDI prediction [70,71]. Our PBPK models overcome these limitations and were built in a more comprehensive and mechanistic approach.…”

“…Warfarin is the substrate of CYP3A4 and CYP2C9. When used in combination with the anti-tumor drugs docetaxel and cyclophosphamide, which inhibit or induce enzymes, the concentration of warfarin in patients will increase or decrease, affecting the Prothrombin Time / International Normalization Ratio (PT-INR), resulting in poor anticoagulant e cacy or increased risk of bleeding.So far, there are several previously published PBPK models of docetaxel, cyclophosphamide, and epirubicin [61,70,71], despite demonstrating reasonable performance, but only the cyclophosphamide PBPK model by Cai et al was applied for DDI prediction, so it is still challenging for DDI prediction.…”

PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies

“… 16 However, a recent evaluation of pyronaridine‐artesunate pharmacokinetics in hamsters, including the development of a minimal PBPK model, indicated AUC lung to AUC blood ratios for pyronaridine of 24.5 on Day 1 and 51.0 on Day 3, supporting the preferential distribution of the drug into the lung. 38 …”

“…During the COVID‐19 pandemic, PBPK modeling was applied to evaluate potential drug repurposing candidates, including the accumulation of drug into ELF and lung mass, similar to the current evaluation. 38 , 42 , 43 , 46 , 47 , 48 , 49 , 50 Notably, PBPK modeling findings were informative in the clinical development of remdesivir. 42 , 50 …”