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Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the
Stephen J Balevic1, Christoph P Hornik1, Thomas P Green1
1From the Department of Rheumatology and Immunology, Duke University School of Medicine, Durham, North Carolina, USA; Duke Clinical Research Institute, Durham, North Carolina, USA; Department of Pediatrics, and the Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Evanston, Illinois, USA; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. This study was supported by the Rheumatology Research Foundation's Scientist Development Award, the Thrasher Research Fund, the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation, the Derfner Foundation, NIGMS/NICHD (2T32GM086330-06), NICHD (5R01-HD076676-04, HHSN275201000003I), and a Duke Health/Private Diagnostic Clinic ENABLE grant. The Atherosclerosis Prevention in Pediatric Lupus Erythematosus [APPLE (ClinicalTrials. gov: NCT00065806)] trial is supported by the US National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) contract N01-AR-2-2265, the Edna and Fred L. Mandel Jr. Center for Hypertension and Atherosclerosis, and Pfizer, which provided atorvastatin and matching placebo. S.J.B. receives support from the NIH (5R01-HD076676-04, 1R01HD083003-01, HHSN275201000003I, HHSN275201800003I, HHSN272201500006I 5U24-TR001608-03), the US Food and Drug Administration (5U18FD006298-03), the Patient-Centered Outcomes Research Institute (PCORI), the Rheumatology Research Foundation's Scientist Development Award, the Thrasher Research Fund, and the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation. C.P.H. receives salary support for research from the National Institute for Child Health and Human Development (NICHD; 1K23HD090239; R13HD102136), National Heart Lung and Blood Institute (R61/R33HL147833), FDA (1R01-FD006099, PI: Laughon; and 5U18-FD006298, PI: Benjamin), the US government for his work in pediatric clinical pharmacology (Government Contract HHSN275201800003I, PI: Benjamin under the Best Pharmaceuticals for Children Act), the nonprofit Burrhoughs Wellcome Fund, and other sponsors for drug development in adults and children (dcri.org/about-us/ conflict-of-interest). D.G. receives support for research from the Eunice Kennedy Shriver NICHD (5R01HD096435). A.M. receives research support from the Thrasher Research Fund (www.thrasherresearch.org). L.E.S. receives support for research from the NIH (U19AR069522), PCORI (8177), and the Childhood Arthritis and Rheumatology Research Alliance. She is on the Data Safety Monitoring Board for investigational product trials for UCB (Cimzia) and Sanofi (sarilumab). Sanofi is a maker of hydroxychloroquine. Samples used in this publication were collected as part of NIH/NIAMS (N01-AR-2-2265). A.M.E. receives support from the NIH National Center for Advancing Translational Sciences. G.K.S. receives support for research from the NIH (UG1 HD068258‑06, HHSN272201300017I, 1UL1TR002553-01, R21AI132677) and the Centers for Disease Control and Prevention (200-2012-53663). She chairs an Independent Data Monitoring Committee for GlaxoSmithKline (RSV vaccine trials). M.C.W. receives support for research from the NIH (1R01-HD076676‑01A1 and 1K24-AI143971), National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), NICHD (HHSN275201000003I), FDA (5U18-FD006298), and the industry for drug development in adults and children. S.J. Balevic, MD, MHS, Department of Rheumatology and Immunology, and Department of Pediatrics, Duke University School of Medicine, and Duke Clinical Research Institute; C.P. Hornik, MD, PhD, Duke Clinical Research Institute, and Department of Pediatrics, Duke University School of Medicine; T.P. Green, MD, MS, Department of Pediatrics, Northwestern University, Feinberg School of Medicine; M.E. Clowse, MD, MPH, Department of Rheumatology and Immunology, Duke University School of Medicine; D. Gonzalez, PharmD, PhD, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill; A.R. Maharaj, PhD, Duke Clinical Research Institute; L.E. Schanberg, MD, Duke Clinical Research Institute, and Department of Pediatrics, Duke University School of Medicine; A.M. Eudy, PhD, Department of Rheumatology and Immunology, Duke University School of Medicine; G.K. Swamy, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Duke University School of Medicine; B.L. Hughes, MD, MSc, Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Duke University School of Medicine; M. Cohen-Wolkowiez, MD, PhD, Duke Clinical Research Institute, and Department of Pediatrics, Duke University School of Medicine. Address correspondence to Dr. S.J. Balevic, Department of Rheumatology and Immunology, Duke University School of Medicine, 2301 Erwin Road, CHC, T-Level, Durham, North Carolina 27710, USA. E-mail: stephen.balevic@duke.edu. Full Release Article. For details see Reprints and Permissions at jrheum. org. Accepted for publication May 14, 2019.
Objective:
To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19).
Methods:
We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2.
Results:
The average total serum/plasma HCQ concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/l in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/l), all studies had about one-tenth the necessary concentration for in vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose.
Conclusion:
We found that the average patient receiving treatment with HCQ for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in vitro. Nevertheless, patients receiving HCQ long term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for HCQ in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for HCQ.
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