Balevic Stephen J, Hornik Christoph P, Green Thomas P, Clowse Megan E B, Gonzalez Daniel, Maharaj Anil R, Schanberg Laura E, Eudy Amanda M, Swamy Geeta K, Hughes Brenna L, Cohen-Wolkowiez Michael
From 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:
J Rheumatol. 2020 May 11. doi: 10.3899/jrheum.200493.
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).
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.
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 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.
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 . 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.
与针对严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）具有报告抗病毒活性的目标浓度相比，对接受长期羟氯喹（HCQ）治疗的风湿病患者的HCQ暴露情况进行特征描述。
我们评估了已发表文献值中的血清和血浆总HCQ浓度、一项儿童系统性红斑狼疮试验中的冷冻血清样本，以及使用已发表的孕期药代动力学模型模拟的浓度。对于每种来源，我们将观察到的或预测的HCQ浓度与针对SARS-CoV-2具有报告抗病毒活性的目标浓度进行比较。
在所有研究中，血清/血浆HCQ平均总浓度均低于0.48mg/l这一最低的SARS-CoV-2目标浓度。假设抗病毒目标暴露最高值（血浆总浓度为4.1mg/l），所有研究的浓度约为病毒抑制所需浓度的十分之一。药代动力学模型模拟证实，接受风湿病常用剂量治疗的孕妇未达到目标暴露水平；然而，模型预测孕期每日一次服用600mg剂量，大多数患者在首剂后将获得最低的中位目标暴露水平。
我们发现，接受HCQ治疗的风湿病患者，包括儿童以及非妊娠/妊娠成人，其血清或血浆总浓度不太可能达到显示可抑制SARS-CoV-2的水平。然而，长期接受HCQ治疗的患者其组织浓度可能远超过血清/血浆浓度。由于SARS-CoV-2背景下HCQ的治疗窗未知，迫切需要开展精心设计的临床试验，纳入风湿病患者，以明确HCQ的疗效、安全性和目标暴露水平。
