摘要
目的
研究抗病毒药物洛匹那韦/利托那韦和阿比多尔在大鼠体内的药代动力学相互作用.
创新点
洛匹那韦/利托那韦联合阿比多尔作为国内多家医疗单位治疗 COVID-19 患者的基础抗病毒方案, 两者的药物相互作用未有研究报道, 本论文通过开展体内药动学实验, 探索合用后药物体内暴露量的改变, 为该方案的临床治疗有效性和安全性提供保障.
方法
建立大鼠洛匹那韦/利托那韦与阿比多尔药动学相互作用模型. 将大鼠分为3组(阿比多尔组、洛匹那韦/利托那韦组及联用组). 洛匹那韦/利托那韦和阿比多尔分别以50 mg/kg/12.5 mg/kg和25 mg/kg灌胃给药. 采用液相色谱串联质谱 (LC-MS/MS) 法测定洛匹那韦和阿比多尔的浓度.
结论
洛匹那韦/利托那韦联合阿比多尔治疗后, 阿比多尔的药时曲线下面积 (AUC) 和洛匹那韦的峰浓度 (Cmax) 显著升高. 这两种药物的相互作用可能会影响联合治疗的安全性. 因此, 洛匹那韦/利托那韦与阿比多尔同时给药时, 建议适当调整给药剂量, 阿比多尔的剂量可能需要减半.
Article PDF
References
Cai QX, Huang DL, Yu H, et al., 2020a. COVID-19: abnormal liver function tests. J Hepatol, 73(3):566–574. https://doi.org/10.1016/j.jhep.2020.04.006
Cai QX, Yang MH, Liu DJ, et al., 2020b. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering (Beijing), 6(10):1192–1198. https://doi.org/10.1016/j.eng.2020.03.007
Cao B, Wang YM, Wen DN, et al., 2020. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med, 382(19):1787–1799. https://doi.org/10.1056/NEJMoa2001282
Deng LS, Li CN, Zeng Q, et al., 2020. Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: a retrospective cohort study. J Infect, 81(1):E1–E5. https://doi.org/10.1016/j.jinf.2020.03.002
Gao JJ, Tian ZX, Yang X, 2020. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends, 14(1):72–73. https://doi.org/10.5582/bst.2020.01047
Gautret P, Lagier JC, Parola P, et al., 2020. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents, 56(1): 105949. https://doi.org/10.1016/j.ijantimicag.2020.105949
Grein J, Ohmagari N, Shin D, et al., 2020. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med, 382(24):2327–2336. https://doi.org/10.1056/NEJMoa2007016
Guo YZ, Xu KJ, Li YT, et al., 2020. Safety of protease inhibitors and Arbidol for SARS-CoV-2 pneumonia in Zhejiang Province, China. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(12):948–954. https://doi.org/10.1631/jzus.B2000204
Jiang SP, Wang RR, Li L, et al., 2020. Liver injury in critically ill and non-critically ill COVID-19 patients: a multicenter, retrospective, observational study. Front Med (Lausanne), 7:347. https://doi.org/10.3389/fmed.2020.00347
Jullien V, Urien S, Hirt D, et al., 2006. Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years. Antimicrob Agents Chemother, 50(11):3548–3555. https://doi.org/10.1128/AAC.00943-05
LiverTox, 2012. Clinical and research information on drug-induced liver injury: protease inhibitors (HIV). Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. https://www.ncbi.nlm.nih.gov/books/NBK548893
Ofotokun I, Chuck SK, Binongo JN, et al., 2007. Lopinavir/ritonavir pharmacokinetic profile: impact of sex and other covariates following a change from twice-daily to once-daily therapy. J Clin Pharmacol, 47(8):970–977. https://doi.org/10.1177/0091270007302564
Umeh OC, Currier JS, Park JG, et al., 2011. Sex differences in lopinavir and ritonavir pharmacokinetics among HIV-infected women and men. J Clin Pharmacol, 51(12): 1665–1673. https://doi.org/10.1177/0091270010388650
Wang ZL, Yang BH, Li QW, et al., 2020. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis, 71 (15):769–777. https://doi.org/10.1093/cid/ciaa272
Xu KJ, Cai HL, Shen YH, et al., 2020. Management of COVID-19: the Zhejiang experience. J Zhejiang Univ (Med Sci), 49(2):147–157 (in Chinese). https://doi.org/10.3785/j.issn.1008-9292.2020.02.02
Zhang C, Shi L, Wang FS, 2020. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol, 5(5):428–430. https://doi.org/10.1016/S2468-1253(20)30057-1
Acknowledgments
This work is supported by the National Natural Science Foundation of China (No. 81703612).
Author information
Authors and Affiliations
Corresponding author
Additional information
Author contributions
Yunzhen HU, Saiping JIANG, and Xiaoyang LU conceived and designed this study. Minjuan ZUO and Xiaojuan WANG carried out the experiments. Yunzhen HU performed data analysis and drafted the manuscript. Rongrong WANG and Lu LI made critical contribution to the discussion. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
Compliance with ethics guidelines
Yunzhen HU, Minjuan ZUO, Xiaojuan WANG, Rongrong WANG, Lu LI, Xiaoyang LU, and Saiping JIANG declare that they have no conflict of interest.
The Research Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) approved the protocol followed in this study. All institutional and national guidelines for the care and use of laboratory animals were followed.
Rights and permissions
About this article
Cite this article
Hu, Y., Zuo, M., Wang, X. et al. Pharmacokinetic interactions between the potential COVID-19 treatment drugs lopinavir/ritonavir and arbidol in rats. J. Zhejiang Univ. Sci. B 22, 599–602 (2021). https://doi.org/10.1631/jzus.B2000728
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1631/jzus.B2000728