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1.
Pharm Res ; 39(1): 57-73, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1615473

ABSTRACT

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.


Subject(s)
Chloroquine/administration & dosage , Chloroquine/pharmacokinetics , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/pharmacokinetics , Respiratory Tract Infections/drug therapy , Virus Diseases/drug therapy , Administration, Inhalation , Aerosols , Algorithms , COVID-19 , Cell Line , Cytosol/metabolism , Humans , Hydrogen-Ion Concentration , Lysosomes/metabolism , Primary Cell Culture
3.
Molecules ; 26(3)2021 Jan 28.
Article in English | MEDLINE | ID: covidwho-1055085

ABSTRACT

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.


Subject(s)
Angiotensin-Converting Enzyme 2 , Chloroquine/chemistry , Hydroxychloroquine/chemistry , Molecular Docking Simulation , Polymorphism, Genetic , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Chloroquine/pharmacokinetics , Chloroquine/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Protein Domains , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
4.
Pharmacol Ther ; 216: 107672, 2020 12.
Article in English | MEDLINE | ID: covidwho-997417

ABSTRACT

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.


Subject(s)
Antimalarials/therapeutic use , Antirheumatic Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antimalarials/pharmacokinetics , Antirheumatic Agents/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19 , Chloroquine/pharmacokinetics , Coronavirus Infections/metabolism , Drug Repositioning , Humans , Malaria/drug therapy , Pandemics , Pneumonia, Viral/metabolism , SARS-CoV-2
6.
Ther Apher Dial ; 25(2): 237-241, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-927093

ABSTRACT

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.


Subject(s)
Chloroquine/pharmacokinetics , Hemofiltration , Hemoperfusion , Hydroxychloroquine/pharmacokinetics , COVID-19/drug therapy , Chromatography, High Pressure Liquid , Humans , In Vitro Techniques
7.
Eur J Clin Pharmacol ; 77(4): 583-593, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-926186

ABSTRACT

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.


Subject(s)
COVID-19/drug therapy , Chloroquine/analogs & derivatives , Drug Repositioning , Models, Biological , Administration, Oral , Adult , Aged , COVID-19/virology , Chloroquine/administration & dosage , Chloroquine/adverse effects , Chloroquine/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Gastrointestinal Absorption , Humans , Male , Metabolic Clearance Rate , Middle Aged , SARS-CoV-2/drug effects
8.
Antimicrob Agents Chemother ; 64(9)2020 08 20.
Article in English | MEDLINE | ID: covidwho-654170

ABSTRACT

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.


Subject(s)
Antimalarials/pharmacology , Chloroquine/pharmacology , Ivermectin/pharmacology , Liver/drug effects , Malaria/drug therapy , Plasmodium cynomolgi/drug effects , Animals , Antimalarials/blood , Antimalarials/pharmacokinetics , Biological Availability , Chloroquine/blood , Chloroquine/pharmacokinetics , Drug Administration Schedule , Drug Combinations , Drug Synergism , Female , Hepatocytes/drug effects , Hepatocytes/parasitology , Ivermectin/blood , Ivermectin/pharmacokinetics , Liver/parasitology , Macaca mulatta , Malaria/parasitology , Male , Parasitemia/drug therapy , Plasmodium cynomolgi/growth & development , Plasmodium cynomolgi/pathogenicity , Primary Cell Culture , Schizonts/drug effects , Schizonts/growth & development
10.
Eur J Drug Metab Pharmacokinet ; 45(6): 715-723, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-709935

ABSTRACT

BACKGROUND AND OBJECTIVES: Chloroquine/hydroxychloroquine has recently been the subject of intense debate regarding its potential antiviral activity against SARS-Cov-2, the etiologic agent of COVID-19. Some report possible curative effects; others do not. Therefore, the objective of this study was to simulate possible scenarios of response to hydroxychloroquine in COVID-19 patients using mathematical modeling. METHODS: To shed some light on this controversial topic, we simulated hydroxychloroquine-based interventions on virus/host cell dynamics using a basic system of previously published differential equations. Mathematical modeling was implemented using Python programming language v 3.7. RESULTS: According to mathematical modeling, hydroxychloroquine may have an impact on the amplitude of the viral load peak and viral clearance if the drug is administered early enough (i.e., when the virus is still confined within the pharyngeal cavity). The effects of chloroquine/hydroxychloroquine may be fully explained only when also considering the capacity of this drug to increase the death rate of SARS-CoV-2-infected cells, in this case by enhancing the cell-mediated immune response. CONCLUSIONS: These considerations may not only be applied to chloroquine/hydroxychloroquine but may have more general implications for development of anti-COVID-19 combination therapies and prevention strategies through an increased death rate of the infected cells.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Betacoronavirus/drug effects , COVID-19 , Chloroquine/pharmacokinetics , Chloroquine/therapeutic use , Coronavirus Infections/metabolism , Humans , Immunity, Cellular/drug effects , Models, Theoretical , Pneumonia, Viral/metabolism , SARS-CoV-2
11.
Am J Med Sci ; 360(6): 618-630, 2020 12.
Article in English | MEDLINE | ID: covidwho-708583

ABSTRACT

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.


Subject(s)
Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chloroquine/therapeutic use , Hydroxychloroquine/therapeutic use , SARS-CoV-2/drug effects , Animals , Antimalarials/pharmacokinetics , Antimalarials/pharmacology , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Chlorocebus aethiops , Chloroquine/pharmacokinetics , Chloroquine/pharmacology , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/pharmacology , Vero Cells
12.
Biomed Pharmacother ; 130: 110582, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-688980

ABSTRACT

Given the speed of viral infection spread, repurposing of existing drugs has been given the highest priority in combating the ongoing COVID-19 pandemic. Only drugs that are already registered or close to registration, and therefore have passed lengthy safety assessments, have a chance to be tested in clinical trials and reach patients quickly enough to help in the current disease outbreak. Here, we have reviewed available evidence and possible ways forward to identify already existing pharmaceuticals displaying modest broad-spectrum antiviral activity which is likely linked to their high accumulation in cells. Several well studied examples indicate that these drugs accumulate in lysosomes, endosomes and biological membranes in general, and thereby interfere with endosomal pathway and intracellular membrane trafficking crucial for viral infection. With the aim to identify other lysosomotropic drugs with possible inherent antiviral activity, we have applied a set of clear physicochemical, pharmacokinetic and molecular criteria on 530 existing drugs. In addition to publicly available data, we have also used our in silico model for the prediction of accumulation in lysosomes and endosomes. By this approach we have identified 36 compounds with possible antiviral effects, also against coronaviruses. For 14 of them evidence of broad-spectrum antiviral activity has already been reported, adding support to the value of this approach. Presented pros and cons, knowledge gaps and methods to identify lysosomotropic antivirals, can help in the evaluation of many drugs currently in clinical trials considered for repurposing to target COVID-19, as well as open doors to finding more potent and safer alternatives.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Drug Repositioning , Lysosomes/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/pharmacokinetics , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Arrhythmias, Cardiac/chemically induced , Azithromycin/pharmacokinetics , Azithromycin/therapeutic use , COVID-19 , Chemical and Drug Induced Liver Injury/etiology , Chloroquine/pharmacokinetics , Chloroquine/therapeutic use , Computer Simulation , Drug Evaluation, Preclinical , Endosomes/drug effects , Humans , Hydrogen-Ion Concentration , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Intracellular Membranes/physiology , Lysosomes/chemistry , Membrane Lipids/metabolism , Models, Biological , Phospholipids/metabolism , SARS-CoV-2 , Surface-Active Agents/pharmacokinetics , Virus Internalization
13.
Am J Emerg Med ; 38(10): 2209-2217, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-665142

ABSTRACT

BACKGROUND: Acute chloroquine and hydroxychloroquine toxicity is characterized by a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias and is associated with significant morbidity and mortality. OBJECTIVE: This review describes acute chloroquine and hydroxychloroquine toxicity, outlines the complex pathophysiologic derangements, and addresses the emergency department (ED) management of this patient population. DISCUSSION: Chloroquine and hydroxychloroquine are aminoquinoline derivatives widely used in the treatment of rheumatologic diseases including systemic lupus erythematosus and rheumatoid arthritis as well as for malaria prophylaxis. In early 2020, anecdotal reports and preliminary data suggested utility of hydroxychloroquine in attenuating viral loads and symptoms in patients with SARS-CoV-2 infection. Aminoquinoline drugs pose unique and significant toxicological risks, both during their intended use as well as in unsupervised settings by laypersons. The therapeutic range for chloroquine is narrow. Acute severe toxicity is associated with 10-30% mortality owing to a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias. Treatment in the ED is focused on decontamination, stabilization of cardiac dysrhythmias, hemodynamic support, electrolyte correction, and seizure prevention. CONCLUSIONS: An understanding of the pathophysiology of acute chloroquine and hydroxychloroquine toxicity and available emergency treatments can assist emergency clinicians in reducing the immediate morbidity and mortality associated with this disease.


Subject(s)
Drug Overdose/therapy , Hydroxychloroquine/poisoning , COVID-19/drug therapy , Chloroquine/pharmacokinetics , Chloroquine/pharmacology , Chloroquine/poisoning , Emergency Service, Hospital , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/pharmacology , Pandemics , SARS-CoV-2
14.
Clin Pharmacol Ther ; 108(6): 1135-1149, 2020 12.
Article in English | MEDLINE | ID: covidwho-657047

ABSTRACT

Chloroquine and hydroxychloroquine are quinoline derivatives used to treat malaria. To date, these medications are not approved for the treatment of viral infections, and there are no well-controlled, prospective, randomized clinical studies or evidence to support their use in patients with coronavirus disease 2019 (COVID-19). Nevertheless, chloroquine and hydroxychloroquine are being studied alone or in combination with other agents to assess their effectiveness in the treatment or prophylaxis for COVID-19. The effective use of any medication involves an understanding of its pharmacokinetics, safety, and mechanism of action. This work provides basic clinical pharmacology information relevant for planning and initiating COVID-19 clinical studies with chloroquine or hydroxychloroquine, summarizes safety data from healthy volunteer studies, and summarizes safety data from phase II and phase II/III clinical studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of azithromycin and chloroquine in combination. In addition, this work presents data describing the proposed mechanisms of action against the severe acute respiratory distress syndrome coronavirus-2 and summarizes clinical efficacy to date.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chloroquine/pharmacology , Chloroquine/therapeutic use , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Age Factors , Aging , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Chloroquine/adverse effects , Chloroquine/pharmacokinetics , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Drug Interactions , Drug Therapy, Combination , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacokinetics , Liver Failure/epidemiology , Malaria/drug therapy , Prospective Studies , Renal Insufficiency/epidemiology , SARS-CoV-2
15.
Rev. saúde pública (Online) ; 54: 68, 2020. graf
Article in English | WHO COVID, LILACS (Americas) | ID: covidwho-637597

ABSTRACT

ABSTRACT 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.


Subject(s)
Humans , Pneumonia, Viral/drug therapy , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Betacoronavirus/drug effects , Hydroxychloroquine/pharmacology , Antimalarials/pharmacology , Chloroquine/adverse effects , Chloroquine/pharmacokinetics , Risk Assessment , Pandemics , Contraindications, Drug , SARS-CoV-2 , COVID-19 , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacokinetics , Antimalarials/adverse effects , Antimalarials/pharmacokinetics
16.
Clin Pharmacol Ther ; 108(5): 1055-1066, 2020 11.
Article in English | MEDLINE | ID: covidwho-277084

ABSTRACT

Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood-stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour-1 (95% CI 0.196-0.230), translating to a parasite clearance half-life of 4.5 hours (95% CI 4.1-5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320-500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing.


Subject(s)
Antimalarials/pharmacokinetics , Chloroquine/pharmacokinetics , Malaria, Vivax/drug therapy , Plasmodium vivax/drug effects , Administration, Oral , Adult , Antimalarials/administration & dosage , Antimalarials/blood , Biotransformation , Chloroquine/administration & dosage , Chloroquine/analogs & derivatives , Chloroquine/blood , Drug Dosage Calculations , Drug Resistance , Female , Humans , Malaria, Vivax/blood , Malaria, Vivax/diagnosis , Malaria, Vivax/parasitology , Male , Models, Biological , Parasite Load , Plasmodium vivax/growth & development , Treatment Outcome , Young Adult
17.
Eur Heart J Acute Cardiovasc Care ; 9(3): 215-221, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-186680

ABSTRACT

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.


Subject(s)
Antimalarials/adverse effects , Betacoronavirus/drug effects , Chloroquine/adverse effects , Coronavirus Infections/drug therapy , Drug Monitoring/methods , Hydroxychloroquine/adverse effects , Pneumonia, Viral/drug therapy , Anti-Bacterial Agents/adverse effects , Antibodies, Monoclonal/adverse effects , Antimalarials/pharmacokinetics , Antimalarials/toxicity , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/complications , COVID-19 , Cardiomyopathies/chemically induced , Cardiomyopathies/complications , Cardiotoxicity/epidemiology , Chloroquine/pharmacokinetics , Chloroquine/toxicity , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/toxicity , Off-Label Use/statistics & numerical data , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Torsades de Pointes/chemically induced , Torsades de Pointes/epidemiology
18.
Am J Transplant ; 20(7): 1896-1901, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-125541

ABSTRACT

The current coronavirus disease 2019 (COVID-19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35-year-old renal transplant recipient who suffered from a severe COVID-19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence-based COVID-19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk-benefit balance of experimental or off-label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID-19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug-drug interactions associated with the various treatment options for COVID-19 in renal transplant patients.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/therapy , Everolimus/pharmacokinetics , Kidney Failure, Chronic/complications , Kidney Transplantation , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Transplant Recipients , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Betacoronavirus , COVID-19 , Chloroquine/administration & dosage , Chloroquine/pharmacokinetics , Drug Combinations , Drug Interactions , Everolimus/administration & dosage , Humans , Immunocompromised Host , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacokinetics , Kidney Failure, Chronic/surgery , Lopinavir/administration & dosage , Lopinavir/pharmacokinetics , Male , Netherlands , Pandemics , Radiography, Thoracic , Ritonavir/administration & dosage , Ritonavir/pharmacokinetics , SARS-CoV-2 , Treatment Outcome
20.
Clin Pharmacol Ther ; 108(2): 248-252, 2020 08.
Article in English | MEDLINE | ID: covidwho-102260

ABSTRACT

As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control coronavirus disease 2019 (COVID-19) experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing World Health Organization (WHO) dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best-evidence to inform pediatric CHQ doses for children infected with COVID-19. A previously developed physiologically-based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID-19 recommended adult dosage regimen of 44 mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in area under the concentration-time curve from zero to 70 hours (AUC0-70h ) the optimal CHQ dose was determined in children of different ages compared with adults. Revised doses were re-introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body-weight based dose is given. As such, we propose the following total cumulative doses: 35 mg/kg (CHQ base) for children 0-1 month, 47 mg/kg for 1-6 months, 55 mg/kg for 6 months-12 years, and 44 mg/kg for adolescents and adults, not to exceed 3,300 mg in any patient. Our study supports age-adjusted CHQ dosing in children with COVID-19 in order to avoid suboptimal or toxic doses. The knowledge-driven, model-informed dose selection paradigm can serve as a science-based alternative to recommend pediatric dosing when pediatric clinical trial data is absent.


Subject(s)
Chloroquine/administration & dosage , Chloroquine/pharmacokinetics , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Body Weight , COVID-19/drug therapy , Child , Child, Preschool , Coronavirus Infections/drug therapy , Humans , Infant , Infant, Newborn , Models, Biological
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