A linked physiologically based pharmacokinetic model for hydroxychloroquine and metabolite desethylhydroxychloroquine in SARS-CoV-2(-)/(+) populations.

Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)-approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well-established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID-19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease-related consequences of SARS-CoV-2 infection/COVID-19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS-CoV-2 infection/COVID-19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS-CoV-2(-)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS-CoV-2(-)/(+)participants, and incorporating COVID-19-associated changes in cytochrome P450 activity did not further improve model performance for the SARS-CoV-2(+) population.

Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions.

In vitro screening for pharmacological activity of existing drugs showed chloroquine and hydroxychloroquine to be effective against severe acute respiratory syndrome coronavirus 2. Oral administration of these compounds to obtain desired pulmonary exposures resulted in dose-limiting systemic toxicity in humans. However, pulmonary drug delivery enables direct and rapid administration to obtain higher local tissue concentrations in target tissue. In this work, inhalable formulations for thermal aerosolization of chloroquine and hydroxychloroquine were developed, and their physicochemical properties were characterized. Thermal aerosolization of 40 mg/mL chloroquine and 100 mg/mL hydroxychloroquine formulations delivered respirable aerosol particle sizes with 0.15 and 0.33 mg per 55 mL puff, respectively. In vitro toxicity was evaluated by exposing primary human bronchial epithelial cells to aerosol generated from Vitrocell. An in vitro exposure to 7.24 µg of chloroquine or 7.99 µg hydroxychloroquine showed no significant changes in cilia beating, transepithelial electrical resistance, and cell viability. The pharmacokinetics of inhaled aerosols was predicted by developing a physiologically based pharmacokinetic model that included a detailed species-specific respiratory tract physiology and lysosomal trapping. Based on the model predictions, inhaling emitted doses comprising 1.5 mg of chloroquine or 3.3 mg hydroxychloroquine three times a day may yield therapeutically effective concentrations in the lung. Inhalation of higher doses further increased effective concentrations in the lung while maintaining lower systemic concentrations. Given the theoretically favorable risk/benefit ratio, the clinical significance for pulmonary delivery of aerosolized chloroquine and hydroxychloroquine to treat COVID-19 needs to be established in rigorous safety and efficacy studies. Graphical abstract.

Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections.

PURPOSE: Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. METHODS: We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. RESULTS: At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. CONCLUSION: Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections.

A New Drug-Drug Interaction Between Hydroxychloroquine and Metformin? A Signal Detection Study.

INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. METHODS: Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. RESULTS: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). CONCLUSION: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.

Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps.

AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.

Drugs in COVID-19 Clinical Trials: Predicting Transporter-Mediated Drug-Drug Interactions Using In Vitro Assays and Real-World Data.

Numerous drugs are currently under accelerated clinical investigation for the treatment of coronavirus disease 2019 (COVID-19); however, well-established safety and efficacy data for these drugs are limited. The goal of this study was to predict the potential of 25 small molecule drugs in clinical trials for COVID-19 to cause clinically relevant drug-drug interactions (DDIs), which could lead to potential adverse drug reactions (ADRs) with the use of concomitant medications. We focused on 11 transporters, which are targets for DDIs. In vitro potency studies in membrane vesicles or HEK293 cells expressing the transporters coupled with DDI risk assessment methods revealed that 20 of the 25 drugs met the criteria from regulatory authorities to trigger consideration of a DDI clinical trial. Analyses of real-world data from electronic health records, including a database representing nearly 120,000 patients with COVID-19, were consistent with several of the drugs causing transporter-mediated DDIs (e.g., sildenafil, chloroquine, and hydroxychloroquine). This study suggests that patients with COVID-19, who are often older and on various concomitant medications, should be carefully monitored for ADRs. Future clinical studies are needed to determine whether the drugs that are predicted to inhibit transporters at clinically relevant concentrations, actually result in DDIs.

Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients.

Hydroxychloroquine (HCQ) appears to be a promising treatment for COVID-19. However, all ongoing clinical trials with HCQ use different dosing regimens, resulting in various concentrations. Pharmacokinetic studies are therefore needed to define the optimal dosing regimen.

Low-dose oral hydroxychloroquine led to impaired vision in a child with renal failure: Case report and literature review.

INTRODUCTION: Hydroxychloroquine (HCQ) has received much attention in the treatment of coronavirus disease 2019 recently. However, it can cause irreversible vision loss. Few cases have been reported in pediatric patient with HCQ-related adverse reactions. Appropriate administration and early disease recognition are important for reducing the adverse drug reactions of HCQ. PATIENT CONCERNS: We report a case of a 14-year-old Chinese girl who sought treatment for rapidly decreasing vision in the left eye over 3 days. The simulation results of the population pharmacokinetic model of HCQ revealed that the plasma concentration of HCQ abnormally increased before the visual acuity of the eye decreased. DIAGNOSIS: She was diagnosed as HCQ related drug adverse reaction. INTERVENTIONS: The daily dose of HCQ for this patient was adjusted from 100 mg/d to 50 mg/d. OUTCOMES: Follow-up for 6 months showed no more vision loss recurrence. However, the existing decreased visual acuity of the eye did not recover either. CONCLUSION: Although decreased visual acuity is an infrequent symptom, ophthalmologists should be aware of the possibility of HCQ concentration enrichment and consider minimizing HCQ use when a child with renal hypofunction seeks treatment for shortsightedness.

Drugs, Metabolites, and Lung Accumulating Small Lysosomotropic Molecules: Multiple Targeting Impedes SARS-CoV-2 Infection and Progress to COVID-19.

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.

Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses.

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.

Chloroquine and Hydroxychloroquine Interact Differently with ACE2 Domains Reported to Bind with the Coronavirus Spike Protein: Mediation by ACE2 Polymorphism.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inducing coronavirus disease 2019 (COVID-19) is still an ongoing challenge. To date, more than 95.4 million have been infected and more than two million deaths have been officially reported by the WHO. Angiotensin-converting enzyme (ACE) plays a key role in the disease pathogenesis. In this computational study, seventeen coding variants were found to be important for ACE2 binding with the coronavirus spike protein. The frequencies of these allele variants range from 3.88 × 10-3 to 5.47 × 10-6 for rs4646116 (K26R) and rs1238146879 (P426A), respectively. Chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are mainly used to prevent and treat malaria and rheumatic diseases. They are also used in several countries to treat SARS-CoV-2 infection inducing COVID-19. Both CQ and HCQ were found to interact differently with the various ACE2 domains reported to bind with coronavirus spike protein. A molecular docking approach revealed that intermolecular interactions of both CQ and HCQ exhibited mediation by ACE2 polymorphism. Further explorations of the relationship and the interactions between ACE2 polymorphism and CQ/HCQ would certainly help to better understand the COVID-19 management strategies, particularly their use in the absence of specific vaccines or drugs.

Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19.

BACKGROUND: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients. METHODS: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2. RESULTS: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs). CONCLUSION: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.

Hydroxychloroquine and COVID-19: a Rheumatologist's Take on the Lessons Learned.

PURPOSE OF REVIEW: Told from the viewpoint of rheumatologists, this review tells the story of hydroxychloroquine and its swift ascent to become a household name as a therapeutic strategy against the novel SARS-CoV-2 virus. This review describes the history, mechanisms, pharmacokinetics, therapeutic applications, and safety profile of hydroxychloroquine as an immunomodulatory and antiviral agent. It also summarizes the major studies that launched and assessed the use of hydroxychloroquine against COVID-19 infection. RECENT FINDINGS: More recent literature calls into question the long-held dogma that endolysosomal alkalinization is the primary mode of action of hydroxychloroquine. Ongoing uncertainty about the multiple potential mechanisms contributing to the therapeutic effect of hydroxychloroquine in rheumatic and viral disease led to a natural avenue for exploration in the treatment of COVID-19. Taken as a whole, the literature does not support utilizing hydroxychloroquine to treat or prevent infection from the SARS-CoV-2 virus. This is, at least in part, due to the wide variability in hydroxychloroquine pharmacokinetics between patients and difficulty achieving adequate target tissue concentrations of hydroxychloroquine without encountering unacceptable toxicities. Hydroxychloroquine continues to be a routinely prescribed, well-tolerated, effective, and low-cost treatment for rheumatic disease. Its therapeutic versatility has led to frequent repurposing for other conditions, most recently as an investigative treatment against the SARS-CoV-2 virus. Despite overall negative findings, the intense study of hydroxychloroquine against COVID-19 infection has enhanced our overall understanding of how hydroxychloroquine operates in autoimmune disease and beyond.

Development of a Physiologically-Based Pharmacokinetic (PBPK) Model of Nebulized Hydroxychloroquine for Pulmonary Delivery to COVID-19 Patients.

Despite inconclusive evidence, chloroquine (CQ) and hydroxychloroquine (HCQ)are commonly used for the treatment of Corona virus Disease 2019(COVID-19) in critically ill patients.It was hypothesized that HCQ as an aerosol application can reach the antiviral concentration of ~1-5 µM in the alveolar cells which has been proven effective in vitro. A physiologically-based pharmacokinetic (PBPK) model of nebulized HCQ for pulmonary delivery to COVID-19 patients using the Nasal-Pulmonary Module in GastroPlus® V9.7 simulator, in order to calculate the necessary inhalation dose regimen of HCQ, was developed. The physiological, drug disposition, and pharmacokinetic parameters were obtained from the literature and used during model building after optimization using Optimization Module, while oral data was used for validation. The 25 mg BID inhalation dosing was predicted to lead to alveolar HCQ levels of 7 µM (above EC50 of ~1-5 µM), and small plasma levels of 0.18 µM (as compared to plasma levels of 3.22 µM after 200 mg BID oral dosing). However, average contact time (>1 µM) is around 0.5 h in lung parts, suggesting indirect exposure response effect of HCQ.The developed PBPK model herein predicted HCQ levels in plasma and different lung parts of adults after multiple inhalation dosing regimens for 5 days. This in-silico work needs to be tested in vivo on healthy subjects and COVID-19 patients using 12.5 mg BID and 25 mg BID inhalation doses.

Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19.

Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.

A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing the coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, achievement of lung concentrations predicted to have in vivo antiviral efficacy might not be possible with the currently proposed oral dosing regimens. Further, high cumulative doses of HCQ raise concerns of systemic toxicity, including cardiotoxicity. Here, we describe a preclinical study to investigate the pharmacokinetics (PKs) of a novel formulation of liposomal HCQ administered by intratracheal (IT) instillation in Sprague-Dawley rats. Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (~ 30-fold) lung exposure, longer (~ 2.5-fold) half-life in lungs, but lower blood exposure with ~ 20% of peak plasma concentration (Cmax ) and 74% of area under the curve from 0 to 72 hours (AUC0-72 ) and lower heart exposure with 23% of Cmax and 58% of AUC0-24 (normalized for dose). Similar results were observed relative to IT administration of unformulated HCQ. These PKs result in an animal model that demonstrated the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

Clearance of chloroquine and hydroxychloroquine by the Seraph® 100 Microbinda Affinity Blood Filter -a device approved for the treatment of COVID-19 patients.

On April 17 2020, the United States Food and Drug Administration granted Coronavirus Disease 2019 (COVID-19) emergency use authorizations for the Seraph 100 Microbind Affinity Blood Filter. The medical device is aimed to treat critically ill COVID-19 patients with confirmed or imminent respiratory failure. The aim of this life size in vitro pharmacokinetic study was to investigate the in vitro adsorption of chloroquine and hydroxychloroquine from human plasma using equipment that is also used at the bedside. After start of the hemoperfusion, Pre (Cpre ) Seraph plasma levels were obtained at 5 (C5 ), 10 (C10 ), 15 (C15 ), 30 (C30 ), 60 (C60 ), and 120 (C120 ) minutes into the procedure. At two timepoints (5 and 120 minutes) post (Cpost ) Seraph plasma levels were determined that were used to calculate the plasma clearance of the Seraph. Both drugs were determined using a validated HPLC method. Median [IQR] plasma clearance of the Seraph for chloroquine/hydroxychloroquine was 1.71 [0.51-4.38] mL/min/1.79 [0.21-3.68] mL/min respectively. The lack of elimination was also confirmed by the fact that plasma levels did not change over the 120 minutes treatment. As neither chloroquine nor hydroxychloroquine were removed by the treatment with the Seraph dose adjustments in COVID-19 patients undergoing this treatment are not necessary.

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.

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.

A multiscale absorption and transit model for oral delivery of hydroxychloroquine: Pharmacokinetic modeling and intestinal concentration prediction to assess toxicity and drug-induced damage in healthy subjects.

Hydroxychloroquine (HCQ) is commonly used in the treatment of malaria and rheumatic diseases. Recently it has also been identified as possible therapeutic option in combating COVID-19. However, the use of HCQ is known to induce cytotoxicity. In 2020, we developed a multiscale absorption and transit (MAT) toolkit to simulate the dissolution, transport, absorption, distribution, metabolism, and elimination of orally administered drugs in the human GIT at multiple levels. MAT was constructed by integrating the spatially accurate first-principles driven high-fidelity drug transport, dissolution, and absorption model in the human stomach and GIT using the recently published Quasi-3D framework. The computational results showed that MAT was able to match the experimental concentration results better than the traditional compartmental models. In this study, we adapted MAT, to predict the pharmacokinetics of orally delivered HCQ in healthy subjects. The computational results matched the experimental concentration results. The simulated stomach and intestinal fluid and enterocyte concentrations were compared with the in vitro CC50 values. While the peak enterocyte concentrations were several orders lower than the in vitro CC50 values, the peak stomach and the intestinal fluid concentrations were only one order smaller than the in vitro CC50 values. In particular, the peak stomach and the duodenum fluid concentrations were just 3× smaller than the in vitro CC50 values. This implies that the lumen walls are much more susceptible to cytotoxicity-based damage than the enterocyte layers. We envision that MAT can be used to optimize the dosing regimen of HCQ by maximizing its bioavailability, while simultaneously minimizing the cytotoxic damage.