Zahr Noël, Urien Saik, Funck-Brentano Christian, Vantomme Hélène, Garcelon Nicolas, Melki Isabelle, Boistault Margaux, Boyer Olivia, Bader-Meunier Brigitte
Clinical Investigation Center, Department of Pharmacology, INSERM, CIC-1901, UMR ICAN 1166, Pitié-Salpêtrière Hospital, Sorbonne Université, AP-HP, F-75013 Paris, France.
Department of Pediatric and Perinatal Pharmacology, Necker Hospital, Université de Paris, AP-HP, F-75015 Paris, France.
Pharmaceuticals (Basel). 2021 Mar 17;14(3):273. doi: 10.3390/ph14030273.
Hydroxychloroquine (HCQ) is an antimalarial agent given to patients with systemic lupus erythematosus (SLE) as first-line therapy. It alleviates childhood-onset systemic lupus erythematosus cSLE skin and musculoskeletal disease, decreasing disease activity and flares. HCQ concentration-effect relationships in children remains unknown. This study aimed to investigate the pharmacokinetics of HCQ and possible concentration-effect relationships.
HCQ blood concentrations and effects were obtained during clinical follow-up on different occasions. cSLE flares were defined using the SLE Disease Activity Index (SLEDAI); flare was denoted by a SLEDAI score > 6. Blood concentration was measured using high-performance liquid chromatography with fluorometric detection. Statistical analysis was performed using a nonlinear mixed-effect approach with the Monolix software.
A total of 168 blood samples were obtained from 55 pediatric patients. HCQ apparent blood clearance (CL/F) was dependent on patients' bodyweight and platelet count. Patients with active cSLE had a lower mean blood HCQ concentration compared with inactive cSLE patients (536 ± 294 vs. 758 ± 490 ng/mL, = 5 × 10). Among patients with HCQ blood concentration ≥750 ng/mL, 87.6% had inactive cSLE. Moreover, HCQ blood concentration was a significant predictor of disease status.
We developed the first HCQ blood concentration-effect relationship for cSLE associated with active or non-active disease status. A prospective randomized study is necessary to confirm these results.
羟氯喹（HCQ）是一种抗疟药，被用作系统性红斑狼疮（SLE）患者的一线治疗药物。它可缓解儿童期起病的系统性红斑狼疮（cSLE）的皮肤和肌肉骨骼疾病，降低疾病活动度和病情发作频率。儿童中HCQ的浓度-效应关系尚不清楚。本研究旨在调查HCQ的药代动力学及可能的浓度-效应关系。
在不同临床随访期间获取HCQ血药浓度及效应数据。使用SLE疾病活动指数（SLEDAI）定义cSLE病情发作；SLEDAI评分>6表示病情发作。采用高效液相色谱荧光检测法测量血药浓度。使用Monolix软件通过非线性混合效应方法进行统计分析。
共从55例儿科患者中采集了168份血样。HCQ的表观血药清除率（CL/F）取决于患者体重和血小板计数。与非活动性cSLE患者相比，活动性cSLE患者的平均血药HCQ浓度较低（536±294 vs. 758±490 ng/mL，P = 5×10⁻⁶）。在HCQ血药浓度≥750 ng/mL的患者中，87.6%为非活动性cSLE。此外，HCQ血药浓度是疾病状态的显著预测指标。
我们建立了首个与活动性或非活动性疾病状态相关的cSLE的HCQ血药浓度-效应关系。需要进行前瞻性随机研究以证实这些结果。
