Systemic exposure to hydroxychloroquine and its relationship with outcome in severely ill COVID‐19 patients in New York City
Alex K Lyashchenko, Yifan Yu, Donald J Mcmahon, Robert Bies, MD Michael T Yin, Orcid ID Serge Cremers
British Journal of Clinical Pharmacology, doi:10.1111/bcp.15489
Aim: To investigate the relationship between systemic exposure to Hydroxychloroquine (HCQ) and its metabolite Desethylhydroxychloroquine (DHCQ) and clinical outcome in severely ill patients treated with a standard oral dose regimen of HCQ during the first wave of COVID-19 in New York City.
Methods: We correlated retrospective clinical data with drug exposure prospectively assessed from convenience samples using population pharmacokinetics and Bayesian estimation. Systemic exposure was assessed in 215 patients admitted to ICU or COVID-ward for whom an interleukin-6 level was requested and who were still alive 24h after the last dose of HCQ. Patients received oral HCQ 600 mg bid on day 1 followed by 4 days of 400 mg qd. Results: Fifty-three% of the patients were intubated at 5.4 ± 6.4 days after admission. 26.5% died at an average of 32.2 ± 19.1 days. QTc at admission was 448 ± 34 msec. Systemic exposure to HCQ and DHCQ demonstrated substantial variability. Cumulative HCQ AUC0-inf =71.4 ± 19.3 h*mg/L and DHCQ AUC0-inf= 56.5 ± 28.3 h*mg/L. Variability in systemic exposure was not clearly explained by renal function, liver function or inflammatory state. In turn, systemic exposure did not correlate with intubation status, survival or QTc prolongation.
Conclusion: This study in severely ill patients was not able to find any relationship between systemic exposure to HCQ and DHCQ and clinical outcome at a routine dose regimen and adds to the growing body of evidence that oral HCQ does not alter the course of disease in COVID-19 patients.
Conflicts of interest None of the authors has a conflict of interest for this work.
References
Al-Kofahi, Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness, Clin Pharmacol Ther,
doi:10.1002/cpt.1874Alvarez, Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application, Pharmaceuticals,
doi:10.3390/ph15020256Barrett, Labbe, Pfister, Application and impact of population pharmacokinetics in the assessment of antiretroviral pharmacotherapy, Clin Pharmacokinet,
doi:10.2165/00003088-200544060-00003Cl/F, Vc, Vp, Ka, Fm et al., 341 Nearest 1 st HCQ MDRD, abnl) n=84
Corral Alaejos, External evaluation of population pharmacokinetic models of imatinib in adults diagnosed with chronic myeloid leukaemia, Br J Clin Pharmacol,
doi:10.1111/bcp.15122Denney, Duvvuri, Buckeridge, Simple, Automatic Noncompartmental Analysis: The PKNCA R Package, J Pharmacokinet Phar
Eveleens Maarse, Effect of hydroxychloroquine on the cardiac ventricular repolarization: A randomized clinical trial, Br J Clin Pharmacol,
doi:10.1111/bcp.15013Funk, Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study, Pediatr Rheumatol Online J,
doi:10.1186/s12969-021-00548-8Garcia-Cremades, Optimizing Hydroxychloroquine Dosing for Patients With COVID-19: An Integrative Modeling Approach for Effective Drug Repurposing, Clin Pharmacol Ther,
doi:10.1002/cpt.1856Geleris, Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2012410Goldman, Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre-COVID-19 reports, Br J Clin Pharmacol,
doi:10.1111/bcp.14546Gulick, Sobieszczyk, Landry, Hollenberg, Prioritizing clinical research studies during the COVID-19 pandemic: lessons from New York City, J Clin Invest,
doi:10.1172/JCI142151Junqueira, Rowe, Efficacy and safety outcomes of proposed randomized controlled trials investigating hydroxychloroquine and chloroquine during the early stages of the COVID-19 pandemic, Br J Clin Pharmacol,
doi:10.1111/bcp.14598Le, Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial, J Antimicrob Chemother,
doi:10.1093/jac/dkaa191Lim, Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax, Antimicrob Agents Chemother,
doi:10.1128/AAC.00339-08Liu, Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19, J Clin Virol,
doi:10.1016/j.jcv.2020.104370Marzolini, Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations, Antimicrob Agents Chemother,
doi:10.1128/AAC.01177-20Nomura, Comprehensive assessment of exposure to clozapine in association with side effects among patients with treatment-resistant schizophrenia: a population pharmacokinetic study, Ther Adv Psychopharmacol,
doi:10.1177/20451253211016189Raj, Population Pharmacokinetics of Hydroxychloroquine Sulfate in Healthcare Workers, Given for Prophylaxis Against Coronavirus Disease 2019 (COVID-19) in India, J Clin Pharmacol,
doi:10.1002/jcph.2092Tang, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ,
doi:10.1136/bmj.m1849Tett, 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.xThemans, Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps, Br J Clin Pharmacol,
doi:10.1111/bcp.14436Vc, Fm, Cl, Apparent volume of distribution of the central compartment for the parent drug; CL/F, Vc/F, Vp/F
Vc, None
Vmetc, None
Vmetp, None
Vp, None
Yao, 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,
doi:10.1093/cid/ciaa237Yeo, Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling, Clin Pharmacol Ther,
doi:10.1002/cpt.1955Zeitlinger, Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents, Clin Pharmacokinet,
doi:10.1007/s40262-020-00924-9{ 'indexed': {'date-parts': [[2022, 8, 12]], 'date-time': '2022-08-12T23:42:05Z', 'timestamp': 1660347725536},
'reference-count': 0,
'publisher': 'Wiley',
'license': [ { 'start': { 'date-parts': [[2022, 8, 12]],
'date-time': '2022-08-12T00:00:00Z',
'timestamp': 1660262400000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'http://onlinelibrary.wiley.com/termsAndConditions#vor'},
{ 'start': { 'date-parts': [[2022, 8, 12]],
'date-time': '2022-08-12T00:00:00Z',
'timestamp': 1660262400000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'http://doi.wiley.com/10.1002/tdm_license_1.1'}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'DOI': '10.1111/bcp.15489',
'type': 'journal-article',
'created': {'date-parts': [[2022, 8, 12]], 'date-time': '2022-08-12T23:09:06Z', 'timestamp': 1660345746000},
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Systemic Exposure to Hydroxychloroquine and its relationship with outcome in severely ill '
'COVID‐19 patients in New York City',
'prefix': '10.1111',
'author': [ { 'ORCID': 'http://orcid.org/0000-0003-0629-0494',
'authenticated-orcid': False,
'given': 'Alex K.',
'family': 'Lyashchenko',
'sequence': 'first',
'affiliation': [ { 'name': 'Department of Pathology and Cell Biology, Vagelos College of '
'Physicians and Surgeons Columbia University Irving Medical '
'Center New York NY United States of America'}]},
{ 'given': 'Yifan',
'family': 'Yu',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmaceutical Sciences University at Buffalo '
'Buffalo NY United States of America'}]},
{ 'given': 'Donald J.',
'family': 'McMahon',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Medicine, Vagelos College of Physicians and '
'Surgeons Columbia University Irving Medical Center New York NY '
'United States of America'}]},
{ 'given': 'Robert',
'family': 'Bies',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmaceutical Sciences University at Buffalo '
'Buffalo NY United States of America'}]},
{ 'given': 'Michael T.',
'family': 'Yin',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Medicine, Vagelos College of Physicians and '
'Surgeons Columbia University Irving Medical Center New York NY '
'United States of America'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-6800-5532',
'authenticated-orcid': False,
'given': 'Serge',
'family': 'Cremers',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmaceutical Sciences University at Buffalo '
'Buffalo NY United States of America'},
{ 'name': 'Department of Medicine, Vagelos College of Physicians and '
'Surgeons Columbia University Irving Medical Center New York NY '
'United States of America'}]}],
'member': '311',
'published-online': {'date-parts': [[2022, 8, 12]]},
'container-title': 'British Journal of Clinical Pharmacology',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.15489',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.15489',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 8, 12]],
'date-time': '2022-08-12T23:09:06Z',
'timestamp': 1660345746000},
'score': 1,
'resource': {'primary': {'URL': 'https://onlinelibrary.wiley.com/doi/10.1111/bcp.15489'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 8, 12]]},
'references-count': 0,
'alternative-id': ['10.1111/bcp.15489'],
'URL': 'http://dx.doi.org/10.1111/bcp.15489',
'relation': {},
'ISSN': ['0306-5251', '1365-2125'],
'subject': ['Pharmacology (medical)', 'Pharmacology'],
'container-title-short': 'Brit J Clinical Pharma',
'published': {'date-parts': [[2022, 8, 12]]}}
