Abstract: Lyashchenko Alex K (Orcid ID: 0000-0003-0629-0494) Cremers Serge (Orcid ID: 0000-0002-6800-5532) Systemic Exposure to Hydroxychloroquine and its relationship with outcome in severely ill COVID-19 patients in New York City Alex K Lyashchenko1, Yifan Yu2, Donald J McMahon3, Robert Bies2, Michael T Yin3, Serge Cremers2,3 1 Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, United States of America 2 Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, United States of America 3 Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, United States of America Corresponding authors: Michael T Yin, MD Associate Professor of Medicine Division of Infectious Diseases Department of Medicine Columbia University Irving Medical Center Email: mty@cumc.columbia.edu Serge Cremers, PharmD, PhD Professor of Pathology and Cell Biology and Medicine Division of Laboratory Medicine Department of Pathology and Cell Biology Columbia University Irving Medical Center This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.15489 This article is protected by copyright. All rights reserved. Email: sc2752@cumc.columbia.edu Running head: PK/PD of Hydroxychloroquine in NYC COVID-19-patients Keywords: COVID-19, Hydroxychloroquine, Pharmacokinetics, Clinical outcome, PK/PD Abstract 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 AUC 0-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. This article is protected by copyright. All rights reserved. What is already known about this subject - Hydroxychloroquine (HCQ) has been used for the treatment of patients with COVID19 infections, especially during the early phase of the..