Progress in drug development for treatment of coronavirus disease 2019 (COVID-19)

Since the outbreak of the novel coronavirus (SARS-CoV-2), the number of people infected worldwide has been increasing, and the medical situation is very severe. In emergency situations, the development of innovative drugs and the treatment of new coronavirus pneumonia (COVID-19) new adaptations on the market The development of the certificate has become the only way to find specific therapeutic drugs and the best treatment plan for COVID-19. The mechanism of angiotensin-converting enzyme 2 (ACE2) that mediates the invasion of host cells by SARS-CoV-2 has been discovered and is based on SARS-CoV- 2. Potential therapeutic targets of host and host, mainly including RNA-dependent RNA polymerase, 3CL protease, papain-like protease, Janus kinase, interleukin 6 and immunomodulators, etc. According to the above-mentioned pharmacological mechanism of action, the treatment of marketed drugs Great progress has been made in the development of new indications for COVID-19 and the clinical research and development of innovative drugs, but no specific drugs have been found. Some traditional Chinese medicines in China can block the SARS-CoV-2 replication cycle, regulate the body's immune response, and treat COVID-19. Biopharmaceuticals are currently undergoing phase I clinical studies in the world for the treatment of COVID-19. Biopharmaceuticals are progressing rapidly, accounting for 67%. At present, the research and development of drugs for the treatment of COVID-19 in China is facing severe challenges and biosafety The number of protection laboratories is small, the research on the mechanism of SARS-CoV-2 infection and the body's response mechanism is not in-depth, the resources of non-clinical cells and animal models are scarce, and the professional quantitative pharmacology research platform and professional talent training system are not perfect to treat COVID-19 The informatization of drug clinical trials and sample testing capabilities are in urgent need of improvement. If China can use this to improve its ability to develop new drugs in emergency situations, it will be able to better protect people's health.

Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients.

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.

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 (RTTCC) 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, RTTCC 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.

Population-based meta-analysis of chloroquine: informing chloroquine pharmacokinetics in COVID-19 patients.

AIMS: Chloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure-efficacy/safety relationship and provide a basis for a possible dosing regimen optimization. SUBJECT AND METHODS: In this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications. RESULTS: A two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h-1, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml). CONCLUSION: Model-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics-pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19.

Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19.

BACKGROUND: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. METHODS: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. RESULTS: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. CONCLUSION: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

Updates on the Pharmacology of Chloroquine against Coronavirus Disease 2019 (COVID-19): A Perspective on its Use in the General and Geriatric Population.

BACKGROUND: Chloroquine has been used to treat malaria for more than 70 years. Its safety profile and cost-effectiveness are well-documented. Scientists have found that chloroquine has in vitro activity against novel coronavirus (SARS-CoV-2). Currently, chloroquine has been adopted in the Protocol for Managing Coronavirus Disease 2019 (COVID-19) (Version 7) issued by the China National Health Commission for clinically managing COVID-19. OBJECTIVE: This review will focus on the antiviral mechanism, effectiveness and safety, dosage and DDIs of chloroquine, for the purpose of providing evidence-based support for rational use of chloroquine in the treatment of COVID-19. METHODS: Use the search terms "chloroquine" linked with "effectiveness", "safety", "mechanism", "drug-drug interaction (DDIs)" or other terms respectively to search relevant literature through PubMed. RESULTS: After searching, we found literature about antivirus mechanism, dosage, DDIs of chloroquine. However, studies on the effectiveness and safety of chloroquine treatment for COVID-19 for the general and geriatric patients are not enough. CONCLUSION: According to literature reports, chloroquine has been proven to have anti-SARS-CoV-2 effect in vitro and the potential mechanism of chloroquine in vivo. Pharmacokinetic characteristics and DDIs study are helpful in guiding rational drug use in general and geriatric patients. Although there have been reports of successful clinical application of chloroquine in the treatment COVID-19, more clinical test data are still needed to prove its effectiveness and safety.

Early forecasting of the potential risk zones of COVID-19 in China's megacities.

Recently, the coronavirus disease 2019 (COVID-19) has become a worldwide public health threat. Early and quick identification of the potential risk zones of COVID-19 infection is increasingly vital for the megacities implementing targeted infection prevention and control measures. In this study, the communities with confirmed cases during January 21-February 27 were collected and considered as the specific epidemic data for Beijing, Guangzhou, and Shenzhen. We evaluated the spatiotemporal variations of the epidemics before utilizing the ecological niche models (ENM) to assemble the epidemic data and nine socioeconomic variables for identifying the potential risk zones of this infection in these megacities. Three megacities were differentiated by the spatial patterns and quantities of infected communities, average cases per community, the percentages of imported cases, as well as the potential risks, although their COVID-19 infection situations have been preliminarily contained to date. With higher risks that were predominated by various influencing factors in each megacity, the potential risk zones coverd about 75% to 100% of currently infected communities. Our results demonstrate that the ENM method was capable of being employed as an early forecasting tool for identifying the potential COVID-19 infection risk zones on a fine scale. We suggest that local hygienic authorities should keep their eyes on the epidemic in each megacity for sufficiently implementing and adjusting their interventions in the zones with more residents or probably crowded places. This study would provide useful clues for relevant hygienic departments making quick responses to increasingly severe epidemics in similar megacities in the world.

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model.

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.

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. METHODS: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2-infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug's safety profile. RESULTS: Hydroxychloroquine (EC50 = 0.72 µM) was found to be more potent than chloroquine (EC50 = 5.47 µM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. CONCLUSIONS: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.