Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials
Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials
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DOI：
10.3899/jrheum.200493
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发表时间：
2020-09-01
影响因子：
3.9
通讯作者：
Cohen-Wolkowiez, Michael
中科院分区：
文献类型：
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作者：
Balevic, Stephen J.;Hornik, Christoph P.;Cohen-Wolkowiez, Michael
客观的。与已报道的针对 SARS-CoV-2 (COVID-19) 引起的 2019 年冠状病毒病的抗病毒活性的目标浓度相比，描述长期接受 HCQ 的风湿性疾病患者的羟氯喹 (HCQ) 暴露情况。方法。我们根据已发表的文献值、儿科系统性红斑狼疮试验的冷冻血清样本以及已发表的妊娠期间药代动力学模型的模拟浓度，评估了血清和血浆中的总 HCQ 浓度。对于每个来源，我们将观察到或预测的 HCQ 浓度与目标浓度以及报告的 SARS-CoV-2 抗病毒活性进行了比较。结果。在所有研究中，平均血清/血浆 HCQ 总浓度均低于 SARS-CoV-2 最低目标 0.48 mg/l。假设最高的抗病毒目标暴露（总血浆浓度为 4.1 mg/l），所有研究的浓度约为体外病毒抑制所需浓度的十分之一。药代动力学模型模拟证实，接受普通剂量治疗风湿性疾病的孕妇未达到目标暴露量；然而，模型预测，对于大多数患者来说，在怀孕期间每天一次 600 毫克的剂量在第一次剂量后将获得最低的中位目标暴露量。结论。我们发现，接受 HCQ 治疗风湿性疾病的普通患者，包括儿童和非怀孕/怀孕成人，不太可能达到体外抑制 SARS-CoV-2 的血清或血浆总浓度。然而，长期接受HCQ的患者的组织浓度可能远远超过血清/血浆。由于 HCQ 在 SARS-CoV-2 背景下的治疗窗口尚不清楚，因此迫切需要包括风湿病患者在内的精心设计的临床试验来表征 HCQ 的有效性、安全性和目标暴露量。
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).Method. 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.