AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France.
AP-HP, Université de Paris, INSERM, Cochin Hospital, Department of Pediatric and Perinatal Pharmacology, 75014 Paris, France.
Therapie. 2021 Jul-Aug;76(4):285-295. doi: 10.1016/j.therap.2021.01.056. Epub 2021 Jan 28.
Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients.
We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2.
HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs).
The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.
羟氯喹（HCQ）达到抑制 SARS-CoV-2 的循环水平所需的剂量是从非 COVID-19 患者的药代动力学数据中推断出来的。
我们对 104 例连续 COVID-19 住院患者（31 例在重症监护病房，73 例在普通病房，共 149 个样本）进行了群体药代动力学分析。使用高效液相色谱法-荧光检测法测定血浆 HCQ 浓度。模型使用 Monolix-2019R2。
HCQ 剂量范围为 200-800mg/天，给药 1-11 天，中位数 HCQ 血浆浓度为 151ng/ml。在测试的协变量中，只有体重影响消除口服清除率（CL）和表观分布容积（Vd）。CL/F（未知生物利用度的 F）和 Vd/F（相对标准误差，%）的估计值分别为 45.9L/h（21.2）和 6690L（16.1）。得出的消除半衰期（t1/2）为 102h。这些参数在 COVID-19 患者中与狼疮患者中的参数不同，后者报告的 CL/F、Vd/F 和 t1/2 分别为 68L/h、2440L 和 19.5h。在 HCQ 开始后 72 小时内，只有 16/104（15.4%）例 COVID-19 患者的 HCQ 血浆水平高于 HCQ 对 SARS-CoV-2 的体外半最大有效浓度（240ng/ml）。HCQ 并未影响炎症状态（通过 C 反应蛋白评估）或 SARS-CoV-2 病毒清除（通过实时逆转录-PCR 鼻咽拭子评估）。
严重 COVID-19 患者 HCQ 药代动力学参数的个体间变异性很大，与非 COVID-19 患者以前报告的参数不同。在≥60%（95%置信区间：49.5-69.0%）的 COVID-19 患者中，需要给予 1600mg HCQ 的负荷剂量，然后每日给予 600mg，才能在 72 小时内达到与抑制 SARS-CoV-2 相关的浓度。
