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1.
Nat Commun ; 12(1): 6370, 2021 11 04.
Article in English | MEDLINE | ID: covidwho-1503481

ABSTRACT

The high efficacy, low cost, and long shelf-life of the ChAdOx1 nCoV-19 vaccine positions it well for use in in diverse socioeconomic settings. Using data from clinical trials, an individual-based model was constructed to predict its 6-month population-level impact. Probabilistic sensitivity analyses evaluated the importance of epidemiological, demographic and logistical factors on vaccine effectiveness. Rollout at various levels of availability and delivery speed, conditional on vaccine efficacy profiles (efficacy of each dose and interval between doses) were explored in representative countries. We highlight how expedient vaccine delivery to high-risk groups is critical in mitigating COVID-19 disease and mortality. In scenarios where the availability of vaccine is insufficient for high-risk groups to receive two doses, administration of a single dose of is optimal, even when vaccine efficacy after one dose is just 75% of the two doses. These findings can help inform allocation strategies particularly in areas constrained by availability.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/analysis , Dose-Response Relationship, Drug , Drug Dosage Calculations , Humans , SARS-CoV-2/genetics , United Kingdom , Vaccination
2.
Ther Drug Monit ; 43(4): 451-454, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1501177

ABSTRACT

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Cefepime/pharmacokinetics , Critical Illness/therapy , Drug Dosage Calculations , Precision Medicine/methods , Acute Kidney Injury/blood , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Cefepime/administration & dosage , Cefepime/adverse effects , Humans , Male , Middle Aged
3.
CPT Pharmacometrics Syst Pharmacol ; 10(10): 1130-1133, 2021 10.
Article in English | MEDLINE | ID: covidwho-1333035

ABSTRACT

Optimal use and distribution of coronavirus disease 2019 (COVID-19) vaccines involves adjustments of dosing. Due to the rapidly evolving pandemic, such adjustments often need to be introduced before full efficacy data are available. As demonstrated in other areas of drug development, quantitative systems pharmacology (QSP) is well placed to guide such extrapolation in a rational and timely manner. Here, we propose for the first time how QSP can be applied in the context of COVID-19 vaccine development.


Subject(s)
COVID-19 Vaccines/administration & dosage , Systems Biology/methods , COVID-19/prevention & control , Drug Dosage Calculations , Humans
4.
Br J Clin Pharmacol ; 87(2): 674-682, 2021 02.
Article in English | MEDLINE | ID: covidwho-1218085

ABSTRACT

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.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Drug Dosage Calculations , Hydroxychloroquine/administration & dosage , Models, Biological , Adult , Aged , Aged, 80 and over , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Arthritis, Rheumatoid/drug therapy , Computer Simulation , Drug Administration Schedule , Female , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacokinetics , Lupus Erythematosus, Systemic/drug therapy , Male , Middle Aged , Monte Carlo Method
5.
Ther Drug Monit ; 43(4): 451-454, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1197045

ABSTRACT

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Cefepime/pharmacokinetics , Critical Illness/therapy , Drug Dosage Calculations , Precision Medicine/methods , Acute Kidney Injury/blood , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Cefepime/administration & dosage , Cefepime/adverse effects , Humans , Male , Middle Aged
6.
Perit Dial Int ; 41(3): 307-312, 2021 05.
Article in English | MEDLINE | ID: covidwho-916958

ABSTRACT

BACKGROUND: Peritoneal dialysis (PD) is a viable option for renal replacement therapy in acute kidney injury (AKI), especially in challenging times during disasters and pandemics when resources are limited. While PD techniques are well described, there is uncertainty about how to determine the amount of PD to be prescribed toward a target dose. The aim of this study is to derive practical equations to assist with the prescription of PD for AKI. METHODS: Using established physiological principles behind PD clearance and membrane transport, a primary determinant of dose delivery, equations were mathematically derived to estimate dialysate volume required to achieve a target dose of PD. RESULTS: The main derivative equation is VD = (1.2 × std-Kt/V × TBW)/(tdwell + 4), where VD is the total dialysate volume per day, std-Kt/V is the desired weekly dose, TBW is the total body water, and tdwell is the dwell time. VD can be expressed in terms of dwell volume, vdwell, by VD = (0.3 × std-Kt/V × TBW) - (6 × vdwell). Two further equations were derived which directly describe the mathematical relationship between tdwell and vdwell. A calculator is included as an Online Supplementary Material. CONCLUSIONS: The equations are intended as a practical tool to estimate solute clearances and guide prescription of continuous PD. The estimated dialysate volume required for any dose target can be calculated from cycle duration or dwell volume. However, the exact target dose of PD is uncertain and should be adjusted according to the clinical circumstances and response to treatment. The equations presented in this article facilitate the adjustment of PD prescription toward the targeted solute clearance.


Subject(s)
Acute Kidney Injury/therapy , Dialysis Solutions/administration & dosage , Peritoneal Dialysis/methods , COVID-19 , Disasters , Drug Dosage Calculations , Humans , Pandemics
7.
J Subst Abuse Treat ; 123: 108276, 2021 04.
Article in English | MEDLINE | ID: covidwho-1139560

ABSTRACT

PURPOSE: Methadone maintenance treatment is a life-saving treatment for people with opioid use disorders (OUD). The coronavirus pandemic (COVID-19) has introduced many concerns surrounding access to opioid treatment. In March 2020, the Substance Abuse and Mental Health Services Administration (SAMHSA) issued guidance allowing for the expansion of take-home methadone doses. We sought to describe changes to treatment experiences from the perspective of persons receiving methadone at outpatient treatment facilities for OUD. METHODS: We conducted an in-person survey among 104 persons receiving methadone from three clinics in central North Carolina in June and July 2020. Surveys collected information on demographic characteristics, methadone treatment history, and experiences with take-home methadone doses in the context of COVID-19 (i.e., before and since March 2020). RESULTS: Before COVID-19, the clinic-level percent of participants receiving any amount of days' supply of take-home doses at each clinic ranged from 56% to 82%, while it ranged from 78% to 100% since COVID-19. The clinic-level percent of participants receiving a take-homes days' supply of a week or longer (i.e., ≥6 days) since COVID-19 ranged from 11% to 56%. Among 87 participants who received take-homes since COVID-19, only four reported selling their take-home doses. CONCLUSIONS: Our study found variation in experiences of take-home dosing by clinic and little diversion of take-home doses. While SAMSHA guidance should allow expanded access to take-home doses, adoption of these guidelines may vary at the clinic level. The adoption of these policies should be explored further, particularly in the context of benefits to patients seeking OUD treatment.


Subject(s)
COVID-19 , Methadone/therapeutic use , Opiate Substitution Treatment , Opioid-Related Disorders/rehabilitation , Patient Satisfaction , SARS-CoV-2 , Adolescent , Adult , Drug Dosage Calculations , Female , Humans , Male , Methadone/administration & dosage , North Carolina , Surveys and Questionnaires , Young Adult
8.
Crit Care Med ; 48(5): e391-e399, 2020 05.
Article in English | MEDLINE | ID: covidwho-661181

ABSTRACT

OBJECTIVES: To investigate the safety, feasibility, and possible adverse events of single-dose human umbilical cord-derived mesenchymal stem cells in patients with moderate-to-severe acute respiratory distress syndrome. DESIGN: Prospective phase I clinical trial. SETTING: Medical center in Kaohsiung, Taiwan. PATIENTS: Moderate-to-severe acute respiratory distress syndrome with a PaO2/FIO2 ratio less than 200. INTERVENTIONS: Scaling for doses was required by Taiwan Food and Drug Administration as follows: the first three patients received low-dose human umbilical cord-derived mesenchymal stem cells (1.0 × 10 cells/kg), the next three patients with intermediate dose (5.0 × 10 cells/kg), and the final three patients with high dose (1.0 × 10 cells/kg) between December 2017 and August 2019. MEASUREMENTS AND MAIN RESULTS: Nine consecutive patients were enrolled into the study. In-hospital mortality was 33.3% (3/9), including two with recurrent septic shock and one with ventilator-induced severe pneumomediastinum and subcutaneous emphysema. No serious prespecified cell infusion-associated or treatment-related adverse events was identified in any patient. Serial flow-cytometric analyses of circulating inflammatory biomarkers (CD14CD33/CD11b+CD16+/CD16+MPO+/CD11b+MPO+/CD14CD33+) and mesenchymal stem cell markers (CD26+CD45-/CD29+CD45-/CD34+CD45-/CD44+CD45-/CD73+CD45-/CD90+CD45-/CD105+CD45-/CD26+CD45-) were notably progressively reduced (p for trend < 0.001), whereas the immune cell markers (Helper-T-cell/Cytotoxity-T-cell/Regulatory-T-cell) were notably increased (p for trend < 0.001) after cell infusion. CONCLUSIONS: The result of this phase I clinical trial showed that a single-dose IV infusion of human umbilical cord-derived mesenchymal stem cells was safe with favorable outcome in nine acute respiratory distress syndrome patients.


Subject(s)
Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/physiology , Respiratory Distress Syndrome/therapy , Umbilical Cord/physiology , Adult , Aged , Drug Dosage Calculations , Female , Hospital Mortality/trends , Humans , Male , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cell Transplantation/mortality , Mesenchymal Stem Cells/classification , Middle Aged , Prospective Studies , Respiratory Distress Syndrome/mortality , Severity of Illness Index
9.
Clin Pharmacol Ther ; 109(4): 1116-1124, 2021 04.
Article in English | MEDLINE | ID: covidwho-1049589

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) disease, including multisystem inflammatory syndrome, has been reported in children. This report summarizes development of a remdesivir physiologically-based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. The adult PBPK model was applied to predict pediatric remdesivir and metabolites steady-state exposures using the Pediatric Population Model in SimCYP and incorporated the relevant physiologic and mechanistic information. Model development was based on adult phase I exposure data in healthy volunteers who were administered a 200-mg loading dose of remdesivir intravenous (IV) over 0.5 hours on Day 1, then 100-mg daily maintenance doses of IV over 0.5 hours starting on Day 2 and continuing through Days 5 or 10. Simulations indicated that use of the adult therapeutic remdesivir dosage regimen (200-mg loading dose on Day 1 then 100-mg daily maintenance dose starting on Day 2) in pediatric patients ≥ 40 kg and a weight-based remdesivir dosage regimen (5-mg/kg loading dose on Day 1 then 2.5-mg/kg daily maintenance dose starting on Day 2) in pediatric patients weighing 2.5 to < 40 kg is predicted to maintain therapeutic exposures of remdesivir and its metabolites. The comprehensive PBPK model described in this report supported remdesivir dosing in planned pediatric clinical studies and dosing in the emergency use authorization and pediatric compassionate use programs that were initiated to support remdesivir as a treatment option during the pandemic.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Adolescent , Alanine/administration & dosage , Alanine/pharmacokinetics , Alanine/therapeutic use , Antiviral Agents/therapeutic use , Area Under Curve , Body Weight , Child , Child, Preschool , Computer Simulation , Drug Dosage Calculations , Female , Humans , Infant , Male , Models, Biological , Pandemics , SARS-CoV-2
10.
J Mol Graph Model ; 104: 107834, 2021 05.
Article in English | MEDLINE | ID: covidwho-1009678

ABSTRACT

Since 2020, the world is facing the first global pandemic of 21st century. Among all the solutions proposed to treat this new strain of coronavirus, named SARS-CoV-2, the vaccine seems a promising way but the delays are too long to be implemented quickly. In the emergency, a dual therapy has shown its effectiveness but has also provoked a set of debates around the dangerousness of a particular molecule, hydroxychloroquine. In particular, the doses to be delivered, according to the studies, were well beyond the acceptable doses to support the treatment without side effects. We propose here to use all the advantages of nanovectorization to address this question of concentration. Using quantum and classical simulations we will show in particular that drug transport on boron nitrogen oxide nanosheets increases the effectiveness of the action of these drugs. This will definitely allow to decrease the drug quantity needing to face the disease.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , Azithromycin/chemistry , Hydroxychloroquine/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Azithromycin/pharmacology , Binding Sites , Boron Compounds/chemistry , COVID-19/drug therapy , COVID-19/virology , Drug Delivery Systems/methods , Drug Dosage Calculations , Humans , Hydroxychloroquine/pharmacology , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Nanomedicine/methods , Nanostructures/chemistry , Nitrogen Oxides/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Quantum Theory , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics
11.
Trials ; 21(1): 919, 2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-917940

ABSTRACT

OBJECTIVES: Assessing the effect of surfactant on clinical outcome in patients with COVID-19 under mechanical ventilation TRIAL DESIGN: Single centre, two arm, parallel group (1:1 allocation ratio), randomised superiority trial with blinded care and outcome assessment. PARTICIPANTS: Inclusion criteria: Adult COVID-19 patients admitted to the ICU in Modarres hospital, Tehran, Iran (age range of 18 to 99 years) with moderate to severe ARDS (based on definition of P/F ratio) requiring auxiliary respiratory devices (either intubation or face mask). EXCLUSION CRITERIA: ● Existence of a major underlying pulmonary disease in addition to COVID-19 ● Underlying congenital heart disease ● Patients needing extracorporeal membrane oxygenation (ECMO) ● ARDS primarily due to any other reason rather than COVID-19 ● The primary source of pulmonary involvement was bacterial pneumonia or any other etiology except for COVID-10 induced lung involvement ● Those who refused to continue the study (either the patient or their family) ● any patient had any sign of healing before entering the study leading to discharge from ICU in less than 12 hours INTERVENTION AND COMPARATOR: In the intervention group, the dose of the drug is a vial containing 4 ml, equivalent to 100 mg, which is prescribed for an adult weighing about 70 kg each time, and if the patient's weight is much lower or higher, it will be adjusted accordingly. Surfactant is prescribed inside the trachea in two doses, starting on the day of intubation with a second dose 6 hours later. The control group will receive the same volume of normal saline, based on weight, administered into the trachea with the same time schedule. MAIN OUTCOMES: 30 days mortality; patient mortality during stay in ICU up to 30 days; ICU length of stay up to 30 days; Time under mechanical ventilation up to 30 days. RANDOMISATION: After the participant enters the study, i.e. after the qualification of the patients in the trial is confirmed and their informed written consent is taken, we will use a simple randomisation method using a table of random numbers. In order to hide the random allocation process, a central randomisation approach will be used and the random sequence will be at the disposal of one of the researchers, excluding the principal investigator. BLINDING (MASKING): Participants, healthcare providers and the principal investigator assessing the outcomes will all be blinded to the group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 60 participants will be randomised in a 1:1 allocation ratio (30 patients allocated to the intervention group and 30 patients allocated to the control group). TRIAL STATUS: The protocol is Version 1.0, May 31, 2020. Recruitment began July 30, 2020, and is anticipated to be completed by October 30, 2020. TRIAL REGISTRATION: IRCT registration number: IRCT20091201002804N12 Registration date: 1st June 2020, 1399/03/12 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Pulmonary Surfactants , Respiration, Artificial/methods , Adult , Betacoronavirus , COVID-19 , Dose-Response Relationship, Drug , Double-Blind Method , Drug Dosage Calculations , Drug Monitoring/methods , Female , Humans , Male , Mortality , Pandemics , Pulmonary Surfactants/administration & dosage , Pulmonary Surfactants/adverse effects , Randomized Controlled Trials as Topic , SARS-CoV-2 , Surface-Active Agents/administration & dosage , Surface-Active Agents/adverse effects , Treatment Outcome
12.
Br J Clin Pharmacol ; 87(4): 2078-2088, 2021 04.
Article in English | MEDLINE | ID: covidwho-883246

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC90 . METHODS: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. RESULTS: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. CONCLUSION: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/prevention & control , Drug Repositioning , Models, Biological , Nitro Compounds/administration & dosage , Thiazoles/administration & dosage , Adult , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , COVID-19/blood , Computer Simulation , Drug Dosage Calculations , Female , Humans , Lung/metabolism , Male , Middle Aged , Nitro Compounds/blood , Nitro Compounds/pharmacokinetics , Reproducibility of Results , Thiazoles/blood , Thiazoles/pharmacokinetics , Tissue Distribution , Young Adult
13.
Clin Pharmacol Ther ; 108(5): 921-923, 2020 11.
Article in English | MEDLINE | ID: covidwho-878708

ABSTRACT

Potential treatments for coronavirus disease 2019 (COVID-19) are being investigated at unprecedented speed, and successful treatments will rapidly be used in tens or hundreds of thousands of patients. To ensure safe and effective use in all those patents it is essential also to develop, at unprecedented speed, a means to provide frequently updated, optimal dosing information for all patient subgroups. Success will require immediate collaboration between drug developers, academics, and regulators.


Subject(s)
Antiviral Agents , Coronavirus Infections , Dose-Response Relationship, Drug , Drug Development , Drug Repositioning , Drug-Related Side Effects and Adverse Reactions , Pandemics , Pneumonia, Viral , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Biological Availability , Biomarkers, Pharmacological/analysis , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Drug Development/methods , Drug Development/standards , Drug Dosage Calculations , Drug Monitoring/standards , Drug Repositioning/methods , Drug Repositioning/standards , Drug-Related Side Effects and Adverse Reactions/blood , Drug-Related Side Effects and Adverse Reactions/prevention & control , Humans , International Cooperation , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Treatment Outcome
14.
Int J Antimicrob Agents ; 56(4): 106144, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-764715

ABSTRACT

Hydroxychloroquine (HCQ) has been largely used and investigated as therapy for COVID-19 across various settings at a total dose usually ranging from 2400 mg to 9600 mg. In Belgium, off-label use of low-dose HCQ (total 2400 mg over 5 days) was recommended for hospitalised patients with COVID-19. We conducted a retrospective analysis of in-hospital mortality in the Belgian national COVID-19 hospital surveillance data. Patients treated either with HCQ monotherapy and supportive care (HCQ group) were compared with patients treated with supportive care only (no-HCQ group) using a competing risks proportional hazards regression with discharge alive as competing risk, adjusted for demographic and clinical features with robust standard errors. Of 8075 patients with complete discharge data on 24 May 2020 and diagnosed before 1 May 2020, 4542 received HCQ in monotherapy and 3533 were in the no-HCQ group. Death was reported in 804/4542 (17.7%) and 957/3533 (27.1%), respectively. In the multivariable analysis, mortality was lower in the HCQ group compared with the no-HCQ group [adjusted hazard ratio (aHR) = 0.684, 95% confidence interval (CI) 0.617-0.758]. Compared with the no-HCQ group, mortality in the HCQ group was reduced both in patients diagnosed ≤5 days (n = 3975) and >5 days (n = 3487) after symptom onset [aHR = 0.701 (95% CI 0.617-0.796) and aHR = 0.647 (95% CI 0.525-0.797), respectively]. Compared with supportive care only, low-dose HCQ monotherapy was independently associated with lower mortality in hospitalised patients with COVID-19 diagnosed and treated early or later after symptom onset.


Subject(s)
Antimalarials/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Betacoronavirus/pathogenicity , C-Reactive Protein/metabolism , COVID-19 , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/mortality , Coronavirus Infections/pathology , Disease Progression , Drug Dosage Calculations , Drug Repositioning , Female , Hospital Mortality , Humans , Intensive Care Units , Male , Middle Aged , Pandemics , Patient Safety , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology , Prognosis , Proportional Hazards Models , Retrospective Studies , SARS-CoV-2 , T-Lymphocytes/pathology , T-Lymphocytes/virology , Tomography, X-Ray Computed , Treatment Outcome
17.
Clin Immunol ; 218: 108517, 2020 09.
Article in English | MEDLINE | ID: covidwho-612038

ABSTRACT

Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/prevention & control , Cytokines/antagonists & inhibitors , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Severe Acute Respiratory Syndrome/prevention & control , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/immunology , Drug Dosage Calculations , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/genetics , Janus Kinase 1/immunology , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/genetics , Janus Kinase 2/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Lung/virology , Nitriles , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/pharmacokinetics , Pyrimidines , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction/drug effects
18.
JAMA Pediatr ; 174(10): e202422, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-540461

ABSTRACT

Importance: Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required. Objective: To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. Design, Setting, and Participants: Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population. Interventions: Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies. Main Outcomes and Measures: The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration. Results: For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL). Conclusions and Relevance: This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Coronavirus Infections/drug therapy , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/pharmacokinetics , Pneumonia, Viral/drug therapy , Therapies, Investigational/methods , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacokinetics , Adolescent , Adult , Alanine/administration & dosage , Alanine/pharmacokinetics , COVID-19 , Child , Child, Preschool , Drug Administration Schedule , Drug Dosage Calculations , Female , Humans , Infant , Infant, Newborn , Male , Models, Biological , Pandemics , Patient Simulation , Young Adult
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