Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
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DOI：
10.1128/aac.01177-20
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发表时间：
2020-09-01
影响因子：
4.9
通讯作者：
Sendi, Parham
中科院分区：
文献类型：
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作者：
Marzolini, Catia;Stader, Felix;Sendi, Parham
冠状病毒病2019年(新冠肺炎)导致炎性细胞因子释放，可以下调代谢酶的表达。这种级联反应会影响血浆中的药物浓度。我们研究了洛匹那韦(LPV)和羟氯喹(HCQ)的血药浓度与急性期炎症标志物C反应蛋白(CRP)水平的关系。前瞻性收集92例住院患者的LPV血药浓度。洛比那韦-利托那韦每12小时给药一次，第1天800/200 mg，第2天400/100 mg，直至第5天或第7天。HCQ每次800 mg，随后在6、24和48h后400 mg，在药物浓度测定当天分析血液学、肝脏、肾脏和炎症实验室指标。研究参与者的平均年龄为59岁(范围从24岁到85岁)，其中71%是男性。从出现症状到住院和开始治疗的中位时间分别为7天(IQR为4~10)和8天(IQR为5~10)。治疗第3天LPV谷值中位数为26.5微克/毫升(IQR为18.9~31.5)。LPV血药浓度与CRP值呈正相关(r=0.37P&t；0.001)，且托西珠单抗治疗前LPV血药浓度显著降低。未发现HCQ浓度与CRP值之间的相关性。新冠肺炎患者存在较高的LPV血药浓度。计算的非结合药物分数与公布的SARS-CoV-2 50%有效浓度(EC50)的比率表明肺内LPV浓度不足。CRP值与LPV显著相关，但与HCQ血浆浓度无关，提示炎症抑制了细胞色素P450 3A4(CYP3A4)的代谢。
Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 mu g/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC50) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.