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1.
Ther Drug Monit ; 43(4): 570-576, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1305442

ABSTRACT

ABSTRACT: Therapeutic drug monitoring of hydroxychloroquine (HCQ) has been recommended to optimize the treatment of patients with COVID-19. The authors describe an ultrahigh-performance liquid chromatography tandem spectrometry method developed in a context of emergency, to analyze HCQ in both human plasma and blood samples. After adding the labeled internal standard and simple protein precipitation, plasma samples were analyzed using a C18 column. Blood samples required evaporation before analysis. The total chromatographic run time was 4 minutes (including 1.5 minutes of column equilibration). The assay was linear over the calibration range (r2 > 0.99) and up to 1.50 mcg/mL for the plasma samples (5.00 mcg/mL for the blood matrix). The limit of quantification was 0.0150 mcg/mL for plasma samples (0.05 mcg/mL blood matrix) with accuracy and precision ranging from 91.1% to 112% and from 0.750% to 11.1%, respectively. Intraday and interday precision and accuracy values were within 15.0%. No significant matrix effect was observed in the plasma or blood samples. This method was successfully applied to patients treated for COVID-19 infection. A simple and rapid ultrahigh-performance liquid chromatography tandem spectrometry method adapted to HCQ therapeutic drug monitoring in the context of SARS-CoV-2 infection was successfully developed and validated.


Subject(s)
COVID-19/drug therapy , Drug Monitoring/standards , Emergency Medical Services/standards , Hydroxychloroquine/blood , Tandem Mass Spectrometry/standards , Antirheumatic Agents/blood , Antirheumatic Agents/therapeutic use , COVID-19/blood , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Chromatography, Liquid/methods , Chromatography, Liquid/standards , Drug Monitoring/methods , Emergency Medical Services/methods , Humans , Hydroxychloroquine/therapeutic use , Pandemics , Tandem Mass Spectrometry/methods
2.
Sci Rep ; 11(1): 8017, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1182869

ABSTRACT

Hydroxychloroquine (2-[[4-[(7-Chloroquinolin-4-yl) amino]pentyl](ethyl) amino]-ethanol, HCQ), an effective anti-malarial drug, has been tested in the clinics for potential treatment of severe coronavirus disease 2019 (COVID-19). Despite the controversy around the clinical benefits of HCQ, the existence of a chiral center in the molecule to possess two optical isomers suggests that there might be an enantiomeric difference on the treatment of COVID-19. Due to their poor resolution and the inability of quantification by previously reported methods for the analysis of HCQ enantiomers, it is necessary to develop an analytical method to achieve baseline separation for quantitative and accurate determination of the enantiomeric purity in order to compare the efficacy and toxicity profiles of different enantiomers. In this study, we developed and validated an accurate and reproducible normal phase chiral high-performance liquid chromatography (HPLC) method for the analysis of two enantiomers of HCQ, and the method was further evaluated with biological samples. With this newly developed method, the relative standard deviations of all analytes were lower than 5%, and the limits of quantification were 0.27 µg/ml, 0.34 µg/ml and 0.20 µg/ml for racemate, R- and S-enantiomer, respectively. The present method provides an essential analytical tool for preclinical and clinical evaluation of HCQ enantiomers for potential treatment of COVID-19.


Subject(s)
Chromatography, High Pressure Liquid , Hydroxychloroquine/analysis , Animals , COVID-19/drug therapy , COVID-19/virology , Humans , Hydroxychloroquine/blood , Hydroxychloroquine/chemistry , Rats , Rats, Sprague-Dawley , Reproducibility of Results , SARS-CoV-2/isolation & purification , Stereoisomerism
3.
PLoS One ; 16(3): e0247356, 2021.
Article in English | MEDLINE | ID: covidwho-1119472

ABSTRACT

BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZM) are antimalarial drugs recently reported to be active against severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2), which is causing the global COVID-19 pandemic. In an emergency response to the pandemic, we aimed to develop a quantitation method for HCQ, its metabolites desethylhydroxychloroquine (DHCQ) and bisdesethylchloroquine (BDCQ), and AZM in human plasma. METHODS: Liquid chromatography tandem mass spectrometry was used to develop the method. Samples (20 µL) are extracted by solid-phase extraction and injected onto the LC-MS/MS system equipped with a PFP column (2.0 × 50 mm, 3 µm). ESI+ and MRM are used for detection. Ion pairs m/z 336.1→247.1 for HCQ, 308.1→179.1 for DHCQ, 264.1→179.1 for BDCQ, and 749.6→591.6 for AZM are selected for quantification. The ion pairs m/z 342.1→253.1, 314.1→181.1, 270.1→181.1, and 754.6→596.6 are selected for the corresponding deuterated internal standards (IS) HCQ-d4, DHCQ-d4, BDCQ-d4, and AZM-d5. The less abundant IS ions from 37Cl were used to overcome the interference from the analytes. RESULTS: Under optimized conditions, retention times are 0.78 min for BDCQ, 0.79 min for DHCQ, 0.92 min for HCQ and 1.87 min for AZM. Total run time is 3.5 min per sample. The calibration ranges are 2-1000 ng/mL for HCQ and AZM, 1-500 ng/mL for DHCQ and 0.5-250 ng/mL for BDCQ; samples above the range are validated for up to 10-fold dilution. Recoveries of the method ranged from 88.9-94.4% for HCQ, 88.6-92.9% for DHCQ, 88.7-90.9% for BDCQ, and 98.6%-102% for AZM. The IS normalized matrix effect were within (100±10) % for all 4 analytes. Blood samples are stable for at least 6 hr at room temperature. Plasma samples are stable for at least 66 hr at room temperature, 38 days at -70°C, and 4 freeze-thaw cycles. CONCLUSIONS: An LC-MS/MS method for simultaneous quantitation of HCQ, DHCQ, BDCQ, and AZM in human plasma was developed and validated for clinical studies requiring fast turnaround time and small samples volume.


Subject(s)
Anti-Bacterial Agents/blood , Antimalarials/blood , Azithromycin/blood , Chloroquine/analogs & derivatives , Hydroxychloroquine/analogs & derivatives , Hydroxychloroquine/blood , Blood Specimen Collection/methods , Chloroquine/blood , Chromatography, High Pressure Liquid/methods , Drug Monitoring/methods , Edetic Acid/blood , Humans , Limit of Detection , Tandem Mass Spectrometry/methods
5.
J Pharm Biomed Anal ; 196: 113935, 2021 Mar 20.
Article in English | MEDLINE | ID: covidwho-1051795

ABSTRACT

BACKGROUND: The present COVID-19 pandemic has prompted worldwide repurposing of drugs. The aim of the present work was to develop and validate a two-dimensional isotope-dilution liquid chromatrography tandem mass spectrometry (ID-LC-MS/MS) method for accurate quantification of remdesivir and its active metabolite GS-441524, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in serum; drugs that have gained attention for repurposing in the treatment of COVID-19. METHODS: Following protein precipitation, samples were separated with a two-dimensional ultra-high performance liquid chromatography (2D-UHPLC) setup, consisting of an online solid phase extraction (SPE) coupled to an analytical column. For quantification, stable isotope-labelled analogues were used as internal standards for all analytes. The method was validated on the basis of the European Medicines Agency bioanalytical method validation protocol. RESULTS: Detuning of lopinavir and ritonavir allowed simultaneous quantification of all analytes with different concentration ranges and sensitivity with a uniform injection volume of 5 µL. The method provided robust validation results with inaccuracy and imprecision values of ≤ 9.59 % and ≤ 11.1 % for all quality controls. CONCLUSION: The presented method is suitable for accurate and simultaneous quantification of remdesivir, its metabolite GS-441525, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in human serum. The quantitative assay may be an efficient tool for the therapeutic drug monitoring of these potential drug candidates in COVID-19 patients in order to increase treatment efficacy and safety.


Subject(s)
Antiviral Agents/blood , Antiviral Agents/therapeutic use , COVID-19/blood , COVID-19/drug therapy , Isotopes/chemistry , SARS-CoV-2/drug effects , Adenosine/analogs & derivatives , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/blood , Alanine/analogs & derivatives , Alanine/blood , Amides/blood , Azithromycin/blood , Chloroquine/blood , Chromatography, Liquid/methods , Furans/blood , Humans , Hydroxychloroquine/blood , Lopinavir/blood , Pandemics/prevention & control , Pyrazines/blood , Pyrroles/blood , Ritonavir/blood , Tandem Mass Spectrometry/methods , Triazines/blood
6.
Clin Biochem ; 89: 70-76, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1032517

ABSTRACT

BACKGROUND: Hydroxychloroquine is an antimalarial drug that has been prescribed for the treatment of patients with COVID-19 infection. To assist in clinician decision-making, several clinical laboratories have developed and validated measurement procedures in-house based on HPLC or HPLC-MS/MS to measure the mass concentration of hydroxychloroquine in different biological fluids. In these cases, laboratories produce their calibration materials but rarely estimate the measurement uncertainty of their assigned values. Thus, we aimed to show how this uncertainty can be calculated, using the preparation of hydroxychloroquine calibrators in blood-hemolysate-based matrix as an example. METHODS: A bottom-up approach was used to estimate the uncertainty related to the values assigned to end-user calibration materials prepared in-house. First, a specification of the measurand and a measurement equation were proposed. Then, different sources of uncertainty related to the preparation of hydroxychloroquine calibration materials were identified and quantified. Afterwards, the combined uncertainty was calculated using the law for the propagation of uncertainty resulting in the final expanded uncertainty. RESULTS: In this study, the most significant source of uncertainty was that associated with the hydroxychloroquine's reference material mass obtained via balance, while the smallest contribution was from the uncertainty associated with the hydroxychloroquine reference material purity. CONCLUSIONS: A simple procedure to estimate the measurement uncertainty of values assigned to calibration materials is presented here, which would be easy to implement in clinical laboratories. Also, it could be put into practice for other pharmacological quantities measured by in-house HPLC or HPLC-MS/MS procedures commonly used in clinical laboratories.


Subject(s)
COVID-19/blood , Chromatography, High Pressure Liquid/methods , Hydroxychloroquine/blood , Antimalarials/administration & dosage , Antimalarials/blood , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Calibration , Chromatography, High Pressure Liquid/standards , Hemolysis , Humans , Hydroxychloroquine/administration & dosage , Quality Control , Reference Standards , SARS-CoV-2/isolation & purification , Uncertainty
8.
Drug Res (Stuttg) ; 71(5): 250-256, 2021 May.
Article in English | MEDLINE | ID: covidwho-997994

ABSTRACT

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.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Hydroxychloroquine/pharmacokinetics , Lung/metabolism , Models, Biological , Administration, Inhalation , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/blood , Lung/drug effects , Nebulizers and Vaporizers , Tissue Distribution
9.
Int J Antimicrob Agents ; 57(2): 106247, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-987980

ABSTRACT

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.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Hydroxychloroquine/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Bronchoalveolar Lavage Fluid/chemistry , Critical Illness , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/blood , Intubation, Gastrointestinal , Lung/drug effects , Lung/virology , Male , Middle Aged , Retrospective Studies , Tablets/administration & dosage , Tablets/pharmacokinetics
10.
Circ Arrhythm Electrophysiol ; 13(10): e008686, 2020 10.
Article in English | MEDLINE | ID: covidwho-982511

ABSTRACT

BACKGROUND: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine is being considered as prophylaxis and treatment of coronavirus disease-19 (COVID-19). Although hydroxychloroquine is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematosus and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. METHODS: To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal ECGs and hydroxychloroquine blood levels were available in a recently completed study evaluating the efficacy of hydroxychloroquine 400 mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro (anti-Sjögren's Syndrome A/Ro) antibodies. RESULTS: Forty-five ECGs were available for corrected QT interval (QTc) measurement, and levels of hydroxychloroquine were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of hydroxychloroquine and the neonatal QTc (R=0.02, P=0.86) or the mean of hydroxychloroquine values obtained throughout each individual pregnancy and the QTc (R=0.04, P=0.80). In total 5 (11% [95% CI, 4%-24%]) neonates had prolongation of the QTc >2 SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. CONCLUSIONS: In aggregate, these data provide reassurances that the maternal use of hydroxychloroquine is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01379573.


Subject(s)
Antiviral Agents/administration & dosage , Electrocardiography , Fetal Heart/drug effects , Heart Block/congenital , Heart Rate/drug effects , Hydroxychloroquine/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/blood , Cardiotoxicity , Drug Administration Schedule , Drug Monitoring , Female , Fetal Blood/metabolism , Fetal Heart/physiopathology , Gestational Age , Heart Block/diagnosis , Heart Block/physiopathology , Heart Block/prevention & control , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/blood , Infant , Infant, Newborn , Male , Predictive Value of Tests , Pregnancy , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome
11.
J Antimicrob Chemother ; 76(2): 482-486, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-939573

ABSTRACT

BACKGROUND: Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with moderate/severe COVID-19 infection. OBJECTIVES: To examine the safety of combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. METHODS: This was an observational cohort study of patients hospitalized for COVID-19 pneumonia treated with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Clinical evaluations, electrocardiograms and the pharmacokinetics of hydroxychloroquine, darunavir and lopinavir were examined according to clinical practice and guidelines. RESULTS: Twenty-one patients received hydroxychloroquine with lopinavir/ritonavir (median age 68 years; 10 males) and 25 received hydroxychloroquine with darunavir/ritonavir (median age 71 years; 15 males). During treatment, eight patients (17.4%) developed ECG abnormalities. Ten patients discontinued treatment, including seven for ECG abnormalities a median of 5 (range 2-6) days after starting treatment. All ECG abnormalities reversed 1-2 days after interrupting treatment. Four patients died within 14 days. ECG abnormalities were significantly associated with age over 70 years, coexisting conditions (such as hypertension, chronic cardiovascular disease and kidney failure) and initial potential drug interactions, but not with the hydroxychloroquine concentration. CONCLUSIONS: Of the patients with COVID-19 who received hydroxychloroquine with lopinavir or darunavir, 17% had ECG abnormalities, mainly related to age or in those with a history of cardiovascular disease.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , Darunavir/adverse effects , Hydroxychloroquine/adverse effects , Lopinavir/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Antiviral Agents/therapeutic use , COVID-19/epidemiology , Cohort Studies , Darunavir/administration & dosage , Darunavir/blood , Darunavir/therapeutic use , Drug Therapy, Combination , Electrocardiography , France , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/blood , Hydroxychloroquine/therapeutic use , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Lopinavir/administration & dosage , Lopinavir/blood , Lopinavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
12.
Ther Drug Monit ; 43(4): 570-576, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-915924

ABSTRACT

ABSTRACT: Therapeutic drug monitoring of hydroxychloroquine (HCQ) has been recommended to optimize the treatment of patients with COVID-19. The authors describe an ultrahigh-performance liquid chromatography tandem spectrometry method developed in a context of emergency, to analyze HCQ in both human plasma and blood samples. After adding the labeled internal standard and simple protein precipitation, plasma samples were analyzed using a C18 column. Blood samples required evaporation before analysis. The total chromatographic run time was 4 minutes (including 1.5 minutes of column equilibration). The assay was linear over the calibration range (r2 > 0.99) and up to 1.50 mcg/mL for the plasma samples (5.00 mcg/mL for the blood matrix). The limit of quantification was 0.0150 mcg/mL for plasma samples (0.05 mcg/mL blood matrix) with accuracy and precision ranging from 91.1% to 112% and from 0.750% to 11.1%, respectively. Intraday and interday precision and accuracy values were within 15.0%. No significant matrix effect was observed in the plasma or blood samples. This method was successfully applied to patients treated for COVID-19 infection. A simple and rapid ultrahigh-performance liquid chromatography tandem spectrometry method adapted to HCQ therapeutic drug monitoring in the context of SARS-CoV-2 infection was successfully developed and validated.


Subject(s)
COVID-19/drug therapy , Drug Monitoring/standards , Emergency Medical Services/standards , Hydroxychloroquine/blood , Tandem Mass Spectrometry/standards , Antirheumatic Agents/blood , Antirheumatic Agents/therapeutic use , COVID-19/blood , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Chromatography, Liquid/methods , Chromatography, Liquid/standards , Drug Monitoring/methods , Emergency Medical Services/methods , Humans , Hydroxychloroquine/therapeutic use , Pandemics , Tandem Mass Spectrometry/methods
13.
Clin Chem Lab Med ; 58(12): 2047-2061, 2020 09 13.
Article in English | MEDLINE | ID: covidwho-760723

ABSTRACT

Objectives Hydroxychloroquine (HCQ) is an anti-malarial and immunomodulatory drug reported to inhibit the Corona virus, SARS-CoV-2, in vitro. At present there is insufficient evidence from clinical trials to determine the safety and efficacy of HCQ as a treatment for COVID-19. However, since the World Health Organisation declared COVID-19 a pandemic in March 2020, the US Food and Drug Administration issued an Emergency Use Authorisation to allow HCQ and Chloroquine (CQ) to be distributed and used for certain hospitalised patients with COVID-19 and numerous clinical trials are underway around the world, including the UK based RECOVERY trial, with over 1000 volunteers. The validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of HCQ and two of its major metabolites, desethylchloroquine (DCQ) and di-desethylchloroquine (DDCQ), in whole blood is described. Methods Blood samples were deproteinised using acetonitrile. HCQ, DCQ and DDCQ were chromatographically separated on a biphenyl column with gradient elution, at a flow rate of 500 µL/min. The analysis time was 8 min. Results For each analyte linear calibration curves were obtained over the concentration range 50-2000 µg/L, the lower limit of quantification (LLOQ) was 13 µg/L, the inter-assay relative standard deviation (RSD) was <10% at 25, 800 and 1750 µg/L and mean recoveries were 80, 81, 78 and 62% for HCQ, d4-HCQ, DCQ and DDCQ, respectively. Conclusion This method has acceptable analytical performance and is applicable to the therapeutic monitoring of HCQ, evaluating the pharmacokinetics of HCQ in COVID-19 patients and supporting clinical trials.


Subject(s)
Blood Chemical Analysis/methods , Chromatography, High Pressure Liquid , Hydroxychloroquine/blood , Hydroxychloroquine/metabolism , Tandem Mass Spectrometry , Calibration , Humans , Limit of Detection , Time Factors
14.
Int J Antimicrob Agents ; 56(5): 106136, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-696144

ABSTRACT

During the Covid-19 pandemic, many intensive care unit (ICU) patients received hydroxychloroquine. The primary objective of this study was to assess the effects of hydroxychloroquine according to its plasma concentration in ICU patients. A single-center retrospective study was performed from March to April 2020 in an ICU of a university hospital. All patients admitted to the ICU with confirmed Covid-19 pneumonia and treated with hydroxychloroquine were included. The study compared 17 patients in whom the hydroxychloroquine plasma concentration was in the therapeutic target (on-target) and 12 patients in whom the plasma concentration was below the target (off-target). The follow-up of patients was 15 days. No association was found between hydroxychloroquine plasma concentration and viral load evolution (P = 0.77). There was no significant difference between the two groups for duration of mechanical ventilation, length of ICU stay, in-hospital mortality, and 15-days mortality. These findings indicate that hydroxychloroquine administration for Covid-19 patients hospitalized in ICU is not associated with improved outcomes. Larger multicenter studies are needed to confirm these results.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/blood , COVID-19 , Critical Care , Female , Hospital Mortality , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/blood , Intensive Care Units , Length of Stay/statistics & numerical data , Male , Middle Aged , Pandemics , Preliminary Data , Retrospective Studies , SARS-CoV-2 , Viral Load/drug effects
16.
Antimicrob Agents Chemother ; 64(9)2020 08 20.
Article in English | MEDLINE | ID: covidwho-639066

ABSTRACT

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 µg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC50) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.


Subject(s)
Antiviral Agents/pharmacokinetics , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Hydroxychloroquine/pharmacokinetics , Lopinavir/pharmacokinetics , Pneumonia, Viral/drug therapy , Ritonavir/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/blood , Antiviral Agents/pharmacology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Drug Administration Schedule , Drug Combinations , Female , Hospitals, University , Humans , Hydroxychloroquine/blood , Hydroxychloroquine/pharmacology , Length of Stay/statistics & numerical data , Lopinavir/blood , Lopinavir/pharmacology , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Retrospective Studies , Ritonavir/blood , Ritonavir/pharmacology , SARS-CoV-2 , Severity of Illness Index , Survival Analysis
17.
Emerg Infect Dis ; 26(10): 2513-2515, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-623269

ABSTRACT

Because of in vitro studies, hydroxychloroquine has been evaluated as a preexposure or postexposure prophylaxis for coronavirus disease (COVID-19) and as a possible COVID-19 curative treatment. We report a case of COVID-19 in a patient with sarcoidosis who was receiving long-term hydroxychloroquine treatment and contracted COVID-19 despite adequate plasma concentrations.


Subject(s)
Antimalarials/therapeutic use , Coronavirus Infections/complications , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/complications , Sarcoidosis, Pulmonary/complications , Sarcoidosis, Pulmonary/drug therapy , Adult , Antimalarials/blood , COVID-19 , Coronavirus Infections/diagnosis , France , Humans , Hydroxychloroquine/blood , Male , Pandemics , Pneumonia, Viral/diagnosis , Time Factors , Tomography, X-Ray Computed
18.
Arthritis Res Ther ; 22(1): 125, 2020 06 01.
Article in English | MEDLINE | ID: covidwho-457521

ABSTRACT

BACKGROUND: Hydroxychloroquine (HCQ) is the standard of care in the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other inflammatory rheumatic diseases and potentially for the treatment in COVID-19 patients. Determination of HCQ for therapeutic drug monitoring (TDM) can be performed in whole blood (WB), serum, and plasma. Direct comparisons of WB, serum, and plasma levels of HCQ in patients with SLE have not previously been reported. We describe a method for the determination of HCQ in human blood using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and compare the suitability of the three sample matrices. METHODS: A method for the determination of HCQ in human blood using LC-HRMS was developed, validated, and applied for the determination of HCQ levels in WB, serum, and plasma from 26 SLE patients. The reproducibility of the method, in the three matrices, was evaluated using quality control samples and repeated preparations and measurements of patient samples. The performance of the developed method for HCQ measurement in serum was further evaluated by comparison with two previously reported extraction methods. RESULTS: The performance of the presented method demonstrated high accuracy and precision. A large range of HCQ concentrations was observed for the SLE patients in all three matrices (WB, serum, and plasma). The mean levels in WB were approximately two-fold the levels in serum and plasma (813 ng/mL compared to 436 ng/mL and 362 ng/mL, respectively). Spiked quality controls showed high reproducibility for all matrices (coefficient of variation, CV, approx. 5%), whereas in patient samples, equally high-precision was only found using WB as the matrix (CV 3%). The CV for serum and plasma was 14% and 39%, respectively. Two alternative methods applied to serum samples did not demonstrate improved precision. CONCLUSIONS: A LC-HRMS method for the measurement of HCQ in human blood was developed and validated. Whole blood was found to be the superior sample matrix in terms of sample reproducibility. Thus, whole blood samples should be used for HCQ analysis when patients are monitored for HCQ treatment effects. The assay is in clinical use to monitor levels of HCQ in patients.


Subject(s)
Betacoronavirus , Coronavirus Infections , Drug Monitoring/standards , Hydroxychloroquine/blood , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/drug therapy , Pandemics , Pneumonia, Viral , Adult , Aged , COVID-19 , Chromatography, Liquid/methods , Chromatography, Liquid/standards , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Drug Monitoring/methods , Female , Humans , Hydroxychloroquine/therapeutic use , Male , Mass Spectrometry/methods , Mass Spectrometry/standards , Middle Aged , Plasma , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Serum , Young Adult
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