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.

A Monoclonal Antibody for Malaria Prevention.

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19.

Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been commonly used for the treatment and prevention of malaria, and the treatment of autoimmune diseases for several decades. As their new mechanisms of actions are identified in recent years, CQ and HCQ have wider therapeutic applications, one of which is to treat viral infectious diseases. Since the pandemic of the coronavirus disease 2019 (COVID-19), CQ and HCQ have been subjected to a number of in vitro and in vivo tests, and their therapeutic prospects for COVID-19 have been proposed. In this article, the applications and mechanisms of action of CQ and HCQ in their conventional fields of anti-malaria and anti-rheumatism, as well as their repurposing prospects in anti-virus are reviewed. The current trials and future potential of CQ and HCQ in combating COVID-19 are discussed.

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization.

BACKGROUND AND OBJECTIVE: In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. METHODS: We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. RESULTS: The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. CONCLUSION: The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.

Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques.

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 µM) and hypnozoites (IC50, 29.24 µM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.

Antimalarials as Antivirals for COVID-19: Believe it or Not!

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for the coronavirus disease -19 (COVID-19). Since December 2019, SARS-CoV-2 has infected millions of people worldwide, leaving hundreds of thousands dead. Chloroquine (CQ) and Hydroxychloroquine (HCQ) are antimalarial medications that have been found to have in vitro efficacy against SARS-CoV-2. Several small prospective studies have shown positive outcomes. However, this result has not been universal, and concerns have been raised regarding the indiscriminate use and potential side effects. The clinicians are conflicted regarding the usage of these medications. Appropriate dose and duration of therapy are unknown. Here, we will discuss the pharmacokinetic and pharmacodynamic properties of CQ and HCQ, as well as review the antiviral properties. The manuscript will also examine the available data from recent clinical and preclinical trials in order to shed light on the apparent inconsistencies.

Primum non nocere - Are chloroquine and hydroxychloroquine safe prophylactic/treatment options for SARS-CoV-2 (covid-19)?

Chloroquine (CQ) and its analog hydroxychloroquine (HCQ) were recently included in several clinical trials as potential prophylactic and therapeutic options for SARS-COV-2 infection/covid-19. However, drug effectiveness in preventing, treating, or slowing the progression of the disease is still unknown. Despite some initial promising in vitro results, rigorous pre-clinical animal studies and randomized clinical trials have not been performed yet. On the other hand, while the potential effectiveness of CQ/HCQ is, at best, hypothetical, their side effects are factual and most worrisome, particularly when considering vulnerable groups of patients being treated with these drugs. in this comment, we briefly explain the possible mechanisms of action of CQ/HCQ for treating other diseases, possible actions against covid-19, and their potent side effects, in order to reinforce the necessity of evaluating the benefit-risk balance when widely prescribing these drugs for SARS-COV-2 infection/covid-19. We conclude by strongly recommending against their indiscriminate use.

Cardiac safety of off-label COVID-19 drug therapy: a review and proposed monitoring protocol.

More than 2,000,000 individuals worldwide have had coronavirus 2019 disease infection (COVID-19), yet there is no effective medical therapy. Multiple off-label and investigational drugs, such as chloroquine and hydroxychloroquine, have gained broad interest due to positive pre-clinical data and are currently used for treatment of COVID-19. However, some of these medications have potential cardiac adverse effects. This is important because up to one-third of patients with COVID-19 have cardiac injury, which can further increase the risk of cardiomyopathy and arrhythmias. Adverse effects of chloroquine and hydroxychloroquine on cardiac function and conduction are broad and can be fatal. Both drugs have an anti-arrhythmic property and are proarrhythmic. The American Heart Association has listed chloroquine and hydroxychloroquine as agents which can cause direct myocardial toxicity. Similarly, other investigational drugs such as favipiravir and lopinavir/ritonavir can prolong QT interval and cause Torsade de Pointes. Many antibiotics commonly used for the treatment of patients with COVID-19, for instance azithromycin, can also prolong QT interval. This review summarizes evidenced-based data regarding potential cardiac adverse effects due to off-label and investigational drugs including chloroquine and hydroxychloroquine, antiviral therapy, monoclonal antibodies, as well as common antibiotics used for the treatment of COVID-19. The article focuses on practical points and offers a point-of-care protocol for providers who are taking care of patients with COVID-19 in an inpatient and outpatient setting. The proposed protocol is taking into consideration that resources during the pandemic are limited.

Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review.

The rapidly spreading Coronavirus Disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), represents an unprecedented serious challenge to the global public health community. The extremely rapid international spread of the disease with significant morbidity and mortality made finding possible therapeutic interventions a global priority. While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. Recent publications have re-examined the use of Chloroquine (CQ) and/or Hydroxychloroquine (HCQ) as a potential therapeutic option for these patients. In an attempt to explore the evidence that supports their use in COVID-19 patients, we comprehensively reviewed the previous studies which used CQ or HCQ as an antiviral treatment. Both CQ and HCQ demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. While few clinical trials have suggested some beneficial effects of CQ and HCQ in COVID-19 patients, most of the reported data are still preliminary. Given the current uncertainty, it is worth being mindful of the potential risks and strictly rationalise the use of these drugs in COVID-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of COVID-19.

Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties.

Since in vitro studies and a preliminary clinical report suggested the efficacy of chloroquine for COVID-19-associated pneumonia, there is increasing interest in this old antimalarial drug. In this article, we discuss the pharmacokinetics and safety of chloroquine that should be considered in light of use in SARS-CoV-2 infections. Chloroquine is well absorbed and distributes extensively resulting in a large volume of distribution with an apparent and terminal half-life of 1.6 days and 2 weeks, respectively. Chloroquine is metabolized by cytochrome P450 and renal clearance is responsible for one third of total clearance. The lack of reliable information on target concentrations or doses for COVID-19 implies that for both adults and children, doses that proved effective and safe in malaria should be considered, such as 'loading doses' in adults (30 mg/kg over 48 h) and children (70 mg/kg over 5 days), which reported good tolerability. Here, plasma concentrations were < 2.5 µmol/L, which is associated with (minor) toxicity. While the influence of renal dysfunction, critical illness, or obesity seems small, in critically ill patients, reduced absorption may be anticipated. Clinical experience has shown that chloroquine has a narrow safety margin, as three times the adult therapeutic dosage for malaria can be lethal when given as a single dose. Although infrequent, poisoning in children is extremely dangerous where one to two tablets can potentially be fatal. In conclusion, the pharmacokinetic and safety properties of chloroquine suggest that chloroquine can be used safely for an acute virus infection, under corrected QT monitoring, but also that the safety margin is small, particularly in children.