Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19
S Ruiz, D Concordet, T Lanot, B Georges, P Goudy, S Baklouti, C Mané, E Losha, H Vinour, D Rousset, M Lavit, V Minville, J-M Conil, P Gandia
International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106247
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.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ijantimicag.2020. 106247 .
References
Boselli, Breilh, Cannesson, Xuereb, Rimmele et al., Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia, Intensive Care Med,
doi:10.1007/s00134-004-2222-8Boselli, Breilh, Saux, Gordien, Allaouchiche, Pharmacokinetics and lung concentrations of ertapenem in patients with ventilator-associated pneumonia, Intensive Care Med,
doi:10.1007/s00134-006-0401-5Brinc, Chan, Venner, Pasic, Colantonio et al., Long-term stability of biochemical markers in pediatric serum specimens stored at -80 °C: a CALIPER Substudy, Clin Biochem,
doi:10.1016/j.clinbiochem.2012.03.029Chhonker, Sleightholm, Li, Oupický, Murry, Simultaneous quantitation of hydroxychloroquine and its metabolites in mouse blood and tissues using LC-ESI-MS/MS: an application for pharmacokinetic studies, J Chromatogr B Analyt Technol Biomed Life Sci,
doi:10.1016/j.jchromb.2017.11.026Devaux, Rolain, Colson, Raoult, New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105938Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105949Gladue, Bright, Isaacson, Newborg, In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection, Antimicrob Agents Chemother,
doi:10.1128/aac.33.3.277Horby, Mafham, Linsell, Bell, Staplin, Effect of hydroxychloroquine in hospitalized patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2022926Inciardi, Lupi, Zaccone, Italia, Raffo et al., Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19), JAMA Cardiol,
doi:10.1001/jamacardio.2020.1096Iwen, Stiles, Pentella, Safety considerations in the laboratory testing of specimens suspected or known to contain the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Am J Clin Pathol,
doi:10.1093/ajcp/aqaa047Kiem, Schentag, Interpretation of antibiotic concentration ratios measured in epithelial lining fluid, Antimicrob Agents Chemother,
doi:10.1128/AAC.00133-06Lim, Im, Cho, Bae, Klein et al., Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax, Antimicrob Agents Chemother,
doi:10.1128/AAC.00339-08Lê, Peiffer-Smadja, Guedj, Náant, Mentrá et al., Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial, J Antimicrob Chemother,
doi:10.1093/jac/dkaa191Ma, Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases, J Antimicrob Chemother,
doi:10.1093/jac/dkv018Maisonnasse, Guedj, Contreras, Behillil, Solas et al., Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates, Nature,
doi:10.1038/s41586-020-2558-4Martin-Blondel, Ruiz, Murris, Faguer, Duhalde et al., Hydroxychloroquine in COVID-19 patients: what still needs to be known about the kinetics, Clin Infect Dis,
doi:10.1093/cid/ciaa558Mimoz, Rolland, Adoun, Marchand, Breilh et al., Steadystate trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg per day in patients with ventilator-associated pneumonia, Intensive Care Med,
doi:10.1007/s00134-006-0136-3Morita, Takahashi, Yoshida, Yokota, Population pharmacokinetics of hydroxychloroquine in Japanese patients with cutaneous or systemic lupus erythematosus, Ther Drug Monit,
doi:10.1097/FTD.0000000000000261Mouton, Theuretzbacher, Tulkens, Derendorf, Cars, Tissue concentrations: do we ever learn?, J Antimicrob Chemother,
doi:10.1093/jac/dkm476Nosál, Ericsson, Sjöqvist, Durisová, Distribution of chloroquine in human blood fractions, Methods Find Exp Clin Pharmacol
Oscanoa, Romero-Ortuno, Carvajal, Savarino, A pharmacological perspective of chloroquine in SARS-CoV-2 infection: an old drug for the fight against a new coronavirus, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.106078Perinel, Launay, Botelho-Nevers, Diconne, Louf-Durier et al., Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients, Clin Infect Dis,
doi:10.1093/cid/ciaa394Rodvold, George, Yoo, Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents, Clin Pharmacokinet,
doi:10.2165/11594090-000000000-00000Tett, Cutler, Day, Brown, A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers, Br J Clin Pharmacol,
doi:10.1111/j.1365-2125.1988.tb05281.xWang, Chen, Lung tissue distribution of drugs as a key factor for COVID-19 treatment, Br J Pharmacol,
doi:10.1111/bph.15102Yao, Ye, Zhang, Cui, Huang et al., In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis,
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'primates',
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'in COVID-19 infection in the DisCoVeRy trial',
'volume': '75',
'author': 'Lê',
'year': '2020',
'journal-title': 'J Antimicrob Chemother'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0007',
'article-title': 'Hydroxychloroquine in COVID-19 patients: what still needs to be known '
'about the kinetics',
'author': 'Martin-Blondel',
'year': '2020',
'journal-title': 'Clin Infect Dis'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0008',
'doi-asserted-by': 'crossref',
'first-page': '2227',
'DOI': '10.1093/cid/ciaa394',
'article-title': 'Towards optimization of hydroxychloroquine dosing in intensive care '
'unit COVID-19 patients',
'volume': '71',
'author': 'Perinel',
'year': '2020',
'journal-title': 'Clin Infect Dis'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0009',
'doi-asserted-by': 'crossref',
'first-page': '303',
'DOI': '10.1111/j.1365-2125.1988.tb05281.x',
'article-title': 'A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine '
'following intravenous administration to healthy volunteers',
'volume': '26',
'author': 'Tett',
'year': '1988',
'journal-title': 'Br J Clin Pharmacol'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0010',
'doi-asserted-by': 'crossref',
'first-page': '1468',
'DOI': '10.1128/AAC.00339-08',
'article-title': 'Pharmacokinetics of hydroxychloroquine and its clinical implications in '
'chemoprophylaxis against malaria caused by Plasmodium vivax',
'volume': '53',
'author': 'Lim',
'year': '2009',
'journal-title': 'Antimicrob Agents Chemother'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0011',
'doi-asserted-by': 'crossref',
'first-page': '1608',
'DOI': '10.1093/jac/dkv018',
'article-title': 'Chloroquine analogues in drug discovery: new directions of uses, '
'mechanisms of actions and toxic manifestations from malaria to '
'multifarious diseases',
'volume': '70',
'author': 'Al-Bari',
'year': '2015',
'journal-title': 'J Antimicrob Chemother'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0012',
'first-page': '581',
'article-title': 'Distribution of chloroquine in human blood fractions',
'volume': '10',
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'year': '1988',
'journal-title': 'Methods Find Exp Clin Pharmacol'},
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'doi-asserted-by': 'crossref',
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'treatment',
'volume': '177',
'author': 'Wang',
'year': '2020',
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'doi-asserted-by': 'crossref',
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'DOI': '10.1093/jac/dkm476',
'article-title': 'Tissue concentrations: do we ever learn?',
'volume': '61',
'author': 'Mouton',
'year': '2008',
'journal-title': 'J Antimicrob Chemother'},
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'article-title': 'Steady-state trough serum and epithelial lining fluid concentrations of '
'teicoplanin 12 mg/kg per day in patients with ventilator-associated '
'pneumonia',
'volume': '32',
'author': 'Mimoz',
'year': '2006',
'journal-title': 'Intensive Care Med'},
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'doi-asserted-by': 'crossref',
'first-page': '2059',
'DOI': '10.1007/s00134-006-0401-5',
'article-title': 'Pharmacokinetics and lung concentrations of ertapenem in patients with '
'ventilator-associated pneumonia',
'volume': '32',
'author': 'Boselli',
'year': '2006',
'journal-title': 'Intensive Care Med'},
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'doi-asserted-by': 'crossref',
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'article-title': 'Interpretation of antibiotic concentration ratios measured in '
'epithelial lining fluid',
'volume': '52',
'author': 'Kiem',
'year': '2008',
'journal-title': 'Antimicrob Agents Chemother'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0018',
'doi-asserted-by': 'crossref',
'first-page': '259',
'DOI': '10.1097/FTD.0000000000000261',
'article-title': 'Population pharmacokinetics of hydroxychloroquine in Japanese patients '
'with cutaneous or systemic lupus erythematosus',
'volume': '38',
'author': 'Morita',
'year': '2016',
'journal-title': 'Ther Drug Monit'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0019',
'doi-asserted-by': 'crossref',
'first-page': '320',
'DOI': '10.1016/j.jchromb.2017.11.026',
'article-title': 'Simultaneous quantitation of hydroxychloroquine and its metabolites in '
'mouse blood and tissues using LC-ESI–MS/MS: an application for '
'pharmacokinetic studies',
'volume': '1072',
'author': 'Chhonker',
'year': '2018',
'journal-title': 'J Chromatogr B Analyt Technol Biomed Life Sci'},
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'doi-asserted-by': 'crossref',
'first-page': '567',
'DOI': '10.1093/ajcp/aqaa047',
'article-title': 'Safety considerations in the laboratory testing of specimens suspected '
'or known to contain the severe acute respiratory syndrome coronavirus 2 '
'(SARS-CoV-2)',
'volume': '153',
'author': 'Iwen',
'year': '2020',
'journal-title': 'Am J Clin Pathol'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0021',
'doi-asserted-by': 'crossref',
'first-page': '816',
'DOI': '10.1016/j.clinbiochem.2012.03.029',
'article-title': 'Long-term stability of biochemical markers in pediatric serum specimens '
'stored at –80 °C: a CALIPER Substudy',
'volume': '45',
'author': 'Brinc',
'year': '2012',
'journal-title': 'Clin Biochem'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0022',
'doi-asserted-by': 'crossref',
'first-page': '976',
'DOI': '10.1007/s00134-004-2222-8',
'article-title': 'Steady-state plasma and intrapulmonary concentrations of '
'piperacillin/tazobactam 4 g/0.5 g administered to critically ill '
'patients with severe nosocomial pneumonia',
'volume': '30',
'author': 'Boselli',
'year': '2004',
'journal-title': 'Intensive Care Med'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0023',
'doi-asserted-by': 'crossref',
'first-page': '637',
'DOI': '10.2165/11594090-000000000-00000',
'article-title': 'Penetration of anti-infective agents into pulmonary epithelial lining '
'fluid: focus on antibacterial agents',
'volume': '50',
'author': 'Rodvold',
'year': '2011',
'journal-title': 'Clin Pharmacokinet'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0024',
'doi-asserted-by': 'crossref',
'first-page': '427',
'DOI': '10.1111/j.1365-2885.2004.00600.x',
'article-title': 'Plasma terminal half-life',
'volume': '27',
'author': 'Toutain',
'year': '2004',
'journal-title': 'J Vet Pharmacol Ther'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0025',
'doi-asserted-by': 'crossref',
'first-page': '830',
'DOI': '10.1038/s41586-020-2312-y',
'article-title': 'The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice',
'volume': '583',
'author': 'Bao',
'year': '2020',
'journal-title': 'Nature'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0026',
'doi-asserted-by': 'crossref',
'first-page': '819',
'DOI': '10.1001/jamacardio.2020.1096',
'article-title': 'Cardiac involvement in a patient with coronavirus disease 2019 '
'(COVID-19)',
'volume': '5',
'author': 'Inciardi',
'year': '2020',
'journal-title': 'JAMA Cardiol'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0027',
'doi-asserted-by': 'crossref',
'DOI': '10.1016/j.ijantimicag.2020.105938',
'article-title': 'New insights on the antiviral effects of chloroquine against '
'coronavirus: what to expect for COVID-19?',
'volume': '55',
'author': 'Devaux',
'year': '2020',
'journal-title': 'Int J Antimicrob Agents'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0028',
'doi-asserted-by': 'crossref',
'first-page': '277',
'DOI': '10.1128/AAC.33.3.277',
'article-title': 'In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic '
'cells: possible mechanism of delivery and release at sites of infection',
'volume': '33',
'author': 'Gladue',
'year': '1989',
'journal-title': 'Antimicrob Agents Chemother'},
{ 'key': '10.1016/j.ijantimicag.2020.106247_bib0029',
'doi-asserted-by': 'crossref',
'first-page': '2030',
'DOI': '10.1056/NEJMoa2022926',
'article-title': 'Effect of hydroxychloroquine in hospitalized patients with Covid-19',
'volume': '383',
'author': 'Horby',
'year': '2020',
'journal-title': 'N Engl J Med'}],
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