Al-Rawi H, Meggitt S J, Williams F M, Wahie S
1 1727 Heart of England NHS Foundation Trust , Department of Dermatology; 92692 Royal Victoria Infirmary , Department of Dermatology, Queen Victoria Road Newcastle upon Tyne NE1 4LP.
2 Royal Victoria Infirmary, Department of Dermatology, Queen Victoria Road, Newcastle upon Tyne NE1 4LP.
Lupus. 2018 Apr;27(5):847-852. doi: 10.1177/0961203317727601. Epub 2017 Sep 1.
Background Hydroxychloroquine (HCQ), a 4-aminoquinolone antimalarial, is regarded as the oral therapy of choice for cutaneous and systemic lupus erythematosus (SLE). It is also licensed for rheumatoid arthritis (RA). Studies of HCQ-treated patients with SLE or RA have demonstrated a positive correlation between whole-blood HCQ levels and clinical response. Such studies have involved measuring whole-blood concentrations at any given time point after HCQ ingestion assuming that steady-state concentrations would undergo limited fluctuation over a daily interval because HCQ has a long half-life. This approach might not sufficiently take into account the potential intra-patient variation in HCQ blood levels that can occur over a 24-hour period. Such variation, if significant, could affect the credibility of any concentration-response relationship provided from these previous studies. Objectives The objectives of this report are to: (a) investigate the intra-patient variation in HCQ whole-blood levels and (b) suggest an optimum time for sampling patients for future studies. Methods Six patients were recruited with cutaneous lupus erythematosus who had each been on HCQ 200 mg twice daily for at least six months, so that they were at steady-state. Each patient was fasted overnight and had standardized meals and dosing schedule. Whole blood was sampled at seven time points over 24 hours. Whole-blood HCQ levels were measured with high-performance liquid chromatography using gradient elution, fluorimetric detection and chloroquine as an internal standard. The assay had a mean inter- and intra-day coefficient of variation of 10% and 5% respectively and a limit of detection of 5ng/ml. Results HCQ levels appeared to follow a biphasic pattern over the sampling period. Maximum levels were noted a median of four hours (range 2-6) after ingestion. Median intra-patient variation between trough and peak levels, 'Cmax' ((peak - trough)/trough × 100%), was 27% (range 8-150%). Conclusions This study demonstrated that whole-blood HCQ levels vary 27% (median, range 8-150%) within an individual over a 12-hour period. Drug levels might differ between individuals because of multiple factors, including variable adherence to medication. Measuring HCQ levels for assessment of drug adherence could be valuable in the 'real-world' clinical setting. This could be assessed by taking a blood sample at any time following HCQ ingestion. If patients were found to have very low or undetectable levels of HCQ, non-adherence to HCQ should be suspected.
背景 羟氯喹（HCQ）是一种4-氨基喹啉类抗疟药，被视为皮肤型和系统性红斑狼疮（SLE）的口服首选治疗药物。它也被批准用于类风湿性关节炎（RA）。对接受HCQ治疗的SLE或RA患者的研究表明，全血HCQ水平与临床反应之间存在正相关。此类研究涉及在HCQ摄入后的任何给定时间点测量全血浓度，假定由于HCQ半衰期长，稳态浓度在一天内波动有限。这种方法可能没有充分考虑到患者体内HCQ血药水平在24小时内可能出现的潜在变化。如果这种变化显著，可能会影响这些先前研究中提供的任何浓度-反应关系的可信度。目的 本报告的目的是：（a）研究患者体内HCQ全血水平的变化，以及（b）为未来研究建议患者采样的最佳时间。方法 招募了6例皮肤型红斑狼疮患者，他们均每日两次服用200mg HCQ至少6个月，因此处于稳态。每位患者过夜禁食，饮食和给药方案标准化。在24小时内的7个时间点采集全血。采用梯度洗脱、荧光检测和以氯喹为内标物的高效液相色谱法测量全血HCQ水平。该测定法的日间和日内变异系数平均值分别为10%和5%，检测限为5ng/ml。结果 在采样期间，HCQ水平似乎呈双相模式。摄入后中位数4小时（范围2 - 6小时）达到最高水平。患者体内谷值与峰值水平之间的中位数变异，即“Cmax”（（峰值 - 谷值）/谷值×100%）为27%（范围8 - 150%）。结论 本研究表明，个体在12小时内全血HCQ水平变化27%（中位数，范围8 - 150%）。由于多种因素，包括用药依从性的差异，个体之间的药物水平可能不同。在“现实世界”临床环境中，测量HCQ水平以评估药物依从性可能有价值。这可以通过在HCQ摄入后的任何时间采集血样来评估。如果发现患者的HCQ水平非常低或无法检测到，应怀疑其未坚持服用HCQ。
