Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure–response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2–5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2–3: 500 mg BID, Days 4–5: 250 mg BID, CQ phosphate), and other vulnerable populations (e.g., renal and hepatic impairment and elderly patients, Days 1–5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0–72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (R_TTCC) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, R_TTCC was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O₂). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.

Aims: This study aims to develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp.Methods: Firstly, physiological information for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug‐dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4 or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults and Caucasian elderly subjects to ensure that drug‐dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observations to evaluate model prediction performance.Results: Ninety‐eight per cent of predicted AUC, 95% of predicted C_max, and 100% of predicted CL values were within two‐fold of the observed values, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60–93. The predicted AUC, C_max, and CL values were all within two‐fold of the observed values.Conclusion: The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, CYP3A4 or eliminated by renal clearance.

A specific, sensitive, and fast method based on high-performance liquid chromatography coupled to tandem mass spectrometry was developed for the determination of atorvastatin and para-hydroxy atorvastatin in human plasma. Solid-phase extraction was used to isolate the compounds from human plasma followed by injection of the extracts onto a C₁₈ column with isocratic elution. The lower limits of quantitation was 0.229 and 0.202 ng/mL for atorvastatin and para-hydroxy atorvastatin in human plasma, respectively. The method was then successfully applied to the pharmacokinetic study of atorvastatin in healthy Chinese male subjects.

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