A pharmacometric approach to evaluate drugs for potential repurposing as COVID-19 therapeutics

References

• Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004 Aug;3(8):673–683.
   Google Scholar
• Dotolo S, Marabotti A, Facchiano A, et al. A review on drug repurposing applicable to COVID-19. Brief Bioinform. 2021 Mar 22;22(2):726–741.
   Google Scholar
• Wu Z, Li W, Liu G, et al. Network-based methods for prediction of drug-target interactions. Front Pharmacol. 2018;9:1134.
   Google Scholar
• Na-Bangchang K, Limpaibul L, Thanavibul A, et al. The pharmacokinetics of chloroquine in healthy Thai subjects and patients with Plasmodium vivax malaria. Br J Clin Pharmacol. 1994 Sep;38(3):278–281.
   Google Scholar
• Boudreau EF, Fleckenstein L, Pang LW, et al. Mefloquine kinetics in cured and recrudescent patients with acute falciparum malaria and in healthy volunteers. Clin Pharmacol Ther. 1990 Oct;48(4):399–409.
   Google Scholar
• Rijken MJ, McGready R, Jullien V, et al. Pharmacokinetics of amodiaquine and desethylamodiaquine in pregnant and postpartum women with Plasmodium vivax malaria. Antimicrob Agents Chemother. 2011 Sep;55(9):4338–4342.
   Google Scholar
• Custodio JM, Chuck SK, Chu H, et al. Lack of clinically important PK interaction between coformulated ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide. Pharmacol Res Perspect. 2017 Oct;5(5):e00353.
   Google Scholar
• Lavielle M, Ilinca E, Kuate R. mlxR: simulation of longitudinal data. R package version 4.2.0. 2021. [cited 2022 Mar 8]. Available from: https://cran.r-project.org/web/packages/mlxR/index.html
   Google Scholar
• RECOVERY Collaborative Group, Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with covid-19. N Engl J Med. 2020 Nov 19;383(21):2030–2040.
   Google Scholar
• Watson JA, Tarning J, Hoglund RM, et al. Concentration-dependent mortality of chloroquine in overdose. Elife. 2020 Jul 8;9. DOI: 10.7554/eLife.58631
   Google Scholar
• Chotsiri P, Tarning J, Hoglund RM, et al. Pharmacometric and electrocardiographic evaluation of chloroquine and azithromycin in healthy volunteers. Clin Pharmacol Ther. 2022 May 22. DOI: 10.1002/cpt.2665
   Google Scholar
• Gustafsson LL, Rombo L, Alvan G, et al. On the question of dose-dependent chloroquine elimination of a single oral dose. Clin Pharmacol Ther. 1983 Sep;34(3):383–385.
   Google Scholar
• Gustafsson LL, Walker O, Alvan G, et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol. 1983 Apr;15(4):471–479.
   Google Scholar
• Hoglund R, Moussavi Y, Ruengweerayut R, et al. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border. Malar J. 2016 Feb 29;15:129.
   Google Scholar
• Obua C, Hellgren U, Ntale M, et al. Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen. Br J Clin Pharmacol. 2008 Apr;65(4):493–501.
   Google Scholar
• Karunajeewa HA, Salman S, Mueller I, et al. Pharmacokinetics of chloroquine and monodesethylchloroquine in pregnancy. Antimicrob Agents Chemother. 2010 Mar;54(3):1186–1192.
   Google Scholar
• Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269–271.
   Google Scholar
• Sacramento CQ, Fintelman-Rodrigues N, Temerozo JR, et al. In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19. J Antimicrob Chemother. 2021 Jun 18;76(7):1874–1885.
   Google Scholar
• Pizzorno A, Padey B, Dubois J, et al. In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Res. 2020 Sep;181:104878.
   Google Scholar
• Jeon S, Ko M, Lee J, et al. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob Agents Chemother. 2020 Jun 23;64(7). DOI: 10.1128/AAC.00819-20.
   Google Scholar
• Kaptein SJF, Jacobs S, Langendries L, et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity. Proc Natl Acad Sci U S A. 2020 Oct 27 117(43):26955–26965.
   Google Scholar
• WHO Solidarity Trial Consortium, Pan H, Peto R, Karim QA, et al. Repurposed antiviral drugs for covid-19 - interim WHO solidarity trial results. N Engl J Med. 2021 Feb 11;384(6):497–511.
   Google Scholar
• White NJ, Watson JA, Hoglund RM, et al. COVID-19 prevention and treatment: a critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. Plos Med. 2020 Sep;17(9):e1003252.
   Google Scholar
• Weinke T, Trautmann M, Held T, et al. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg. 1991 Jul;45(1):86–91.
   Google Scholar
• Guidi M, Mercier T, Aouri M, et al. Population pharmacokinetics and pharmacodynamics of the artesunate-mefloquine fixed dose combination for the treatment of uncomplicated falciparum malaria in African children. Malar J. 2019 Apr 18 18(1):139.
   Google Scholar
• Hoglund RM, Ruengweerayut R, Na-Bangchang K. Population pharmacokinetics of mefloquine given as a 3-day artesunate-mefloquine in patients with acute uncomplicated Plasmodium falciparum malaria in a multidrug-resistant area along the Thai-Myanmar border. Malar J. 2018 Sep 3; 17(1):322.
   Google Scholar
• Reuter SE, Upton RN, Evans AM, et al. Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother. 2015 Mar;70(3):868–876.
   Google Scholar
• Valea I, Tinto H, Traore-Coulibaly M, et al. Pharmacokinetics of co-formulated mefloquine and artesunate in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum infection in Burkina Faso. J Antimicrob Chemother. 2014 Sep;69(9):2499–2507.
   Google Scholar
• Gendrot M, Andreani J, Boxberger M, et al. Antimalarial drugs inhibit the replication of SARS-CoV-2: an in vitro evaluation. Travel Med Infect Dis. 2020 Sep - Oct;37:101873.
   Google Scholar
• Gendrot M, Duflot I, Boxberger M, et al. Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: in vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate. Int J Infect Dis. 2020 Oct;99:437–440.
   Google Scholar
• Jones R, Kunsman G, Levine B, et al. Mefloquine distribution in postmortem cases. Forensic Sci Int. 1994 Sep 6;68(1):29–32.
   Google Scholar
• WHO Policy Recommendation. Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa: world health organization. 2012. [cited 2022 Mar 8]. Available from: https://apps.who.int/iris/bitstream/handle/10665/337978/WHO-HTM-GMP-2012.02-eng.pdf?sequence=1&isAllowed=y
   Google Scholar
• Tarning J, Chotsiri P, Jullien V, et al. Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy. Antimicrob Agents Chemother. 2012 Nov;56(11):5764–5773.
   Google Scholar
• Ali AM, Penny MA, Smith TA, et al. Population pharmacokinetics of the antimalarial amodiaquine: a pooled analysis to optimize dosing. Antimicrob Agents Chemother. 2018 Oct;62(10). 10.1128/AAC.02193-17.
   Google Scholar
• Winstanley PA, Edwards G, Curtis CG, et al. Tissue distribution and excretion of amodiaquine in the rat. J Pharm Pharmacol. 1988 May;40(5):343–349.
   Google Scholar
• Gandhi Y, Eley T, Fura A, et al. Daclatasvir: a review of preclinical and clinical pharmacokinetics. Clin Pharmacokinet. 2018 Aug;57(8):911–928.
   Google Scholar
• Chan P, Li H, Zhu L, et al. Population pharmacokinetic analysis of Daclatasvir in subjects with chronic hepatitis C virus infection. Clin Pharmacokinet. 2017 Oct;56(10):1173–1183.
   Google Scholar
• Osawa M, Ueno T, Ishikawa H, et al. Population pharmacokinetic analysis for Daclatasvir and asunaprevir in Japanese subjects with chronic hepatitis C virus infection. J Clin Pharmacol. 2018 Nov;58(11):1468–1478.
   Google Scholar
• Osawa M, Ueno T, Shiozaki T, et al. Population pharmacokinetic analysis of Daclatasvir, asunaprevir, and beclabuvir combination in HCV-Infected subjects. Clin Pharmacol Drug Dev. 2019 Aug;8(6):802–817.
   Google Scholar
• Shen Z, Zhu X, Zhang H, et al. Pharmacokinetic profile of a generic formulation of sofosbuvir and its metabolite GS-331007 in healthy Chinese subjects. Clin Pharmacol Drug Dev. 2019 Nov;8(8):1073–1080.
   Google Scholar
• Jin F, Kirby B, Gao Y, et al. Population pharmacokinetic modeling of sofosbuvir, an NS5B polymerase inhibitor, and its metabolites in patients with hepatitis C virus infection. In: Population Approach Group in Europe (PAGE-meeting). Crete Greece:Hersonissos; 2015
   Google Scholar
• Abbaspour Kasgari H, Moradi S, Shabani AM, et al. Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial. J Antimicrob Chemother. 2020 Nov 1;75(11):3373–3378.
   Google Scholar
• Khalili H, Nourian A, Ahmadinejad Z, et al. Efficacy and safety of sofosbuvir/ ledipasvir in treatment of patients with COVID-19; A randomized clinical trial. Acta Biomed. 2020 Nov 10;91(4):e2020102.
   Google Scholar
• Zein A, Sulistiyana CS, Raffaello WM, et al. Sofosbuvir with daclatasvir and the outcomes of patients with COVID-19: a systematic review and meta-analysis with GRADE assessment. Postgrad Med J. 2021;98(1161):509–514.
   Google Scholar
• Pertinez H, Rajoli RKR, Khoo SH, et al. Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5’-triphosphate exposure to support posology for SARS-CoV-2. J Antimicrob Chemother. 2021 Jul 15;76(8):2121–2128.
   Google Scholar
• Wang Y, Zhong W, Salam A, et al. Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza. EBio Med. 2020 Dec;62:103125.
   Google Scholar
• Udwadia ZF, Singh P, Barkate H, et al. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis. 2021 Feb;103:62–71.
   Google Scholar
• Kelleni MT. NSAIDs/nitazoxanide/azithromycin repurposed for COVID-19: potential mitigation of the cytokine storm interleukin-6 amplifier via immunomodulatory effects. Expert Rev Anti Infect Ther. 2022 Jan;20(1):17–21.
   Google Scholar
• ALINIA [product monograph] Tampa FL. Romark L.C. 2005. [cited 2022 Mar 8]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021818lbl.pdf
   Google Scholar
• Broekhuysen J, Stockis A, Lins RL, et al. Nitazoxanide: pharmacokinetics and metabolism in man. Int J Clin Pharmacol Ther. 2000 Aug;38(8):387–394.
   Google Scholar
• Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014 Oct;110:94–103.
   Google Scholar
• Rajoli RK, Pertinez H, Arshad U, et al. Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. medRxiv. 2020 May 6
   Google Scholar
• Marcelin-Jimenez G, Contreras-Zavala L, Maggi-Castellanos M, et al. Development of a method by UPLC-MS/MS for the quantification of tizoxanide in human plasma and its pharmacokinetic application. Bioanalysis. 2012 May;4(8):909–917.
   Google Scholar
• Balderas-Acata JI, Ríos-Rogríguez Bueno EP, Pérez-Becerril F, et al. Bioavailability of two oral-suspension formulations of a single dose of nitazoxanide 500 mg: an open-label, randomized-sequence, two-period crossover, comparison in healthy fasted Mexican adult volunteers [research article]. J Bioequivalence Bioavailability. 2011;3(3):043–047.
   Google Scholar
• STROMECTOL [product monograph] Kirkland QC. Canada: Merck Canada Inc.; 2018. [cited 2022 Mar 8]. Available from: https://www.merck.ca/static/pdf/STROMECTOL-PM_E.pdf
   Google Scholar
• Wishart DS, Knox C, Guo AC, et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006 Jan 1;34( Database issue):D668–72.
   Google Scholar
• Gonzalez Canga A, Sahagun Prieto AM, Diez Liebana MJ, et al. The pharmacokinetics and interactions of ivermectin in humans–a mini-review. AAPS J. 2008;10(1):42–46.
   Google Scholar
• Tipthara P, Kobylinski KC, Godejohann M, et al. Identification of the metabolites of ivermectin in humans. Pharmacol Res Perspect. 2021 Feb;9(1):e00712.
   Google Scholar
• El-Tahtawy A, Glue P, Andrews EN, et al. The effect of azithromycin on ivermectin pharmacokinetics–a population pharmacokinetic model analysis. PLoS Negl Trop Dis. 2008 May 14;2(5):e236.
   Google Scholar
• Duthaler U, Suenderhauf C, Karlsson MO, et al. Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers. Br J Clin Pharmacol. 2019 Mar;85(3):626–633.
   Google Scholar
• Gwee A, Duffull S, Zhu X, et al. Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children. PLoS Negl Trop Dis. 2020 Dec;14(12):e0008886.
   Google Scholar
• Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787.
   Google Scholar
• REYATAZ [product monograph]. Montreal Canada: Bristol-Myers Squibb Canada Co.; 2020. [cited 2022 Mar 8]. Available from: https://www.bms.com/assets/bms/ca/documents/productmonograph/REYATAZ_EN_PM.pdf
   Google Scholar
• Fintelman-Rodrigues N, Sacramento CQ, Lima CR,et al . (2020). Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production. Antimicrob Agents Chemother, 64(10), 10.1128/AAC.00825-20
   Google Scholar
• Yamamoto N, Matsuyama S, Hoshino T,et al. Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro. bioRxiv: 2020.04.06.026476.
   Google Scholar
• Le Tiec C, Barrail A, Goujard C, et al. Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin Pharmacokinet. 2005;44(10):1035–1050.
   Google Scholar
• Dickinson L, Boffito M, Back D, et al. Population pharmacokinetics of ritonavir-boosted atazanavir in HIV-infected patients and healthy volunteers. J Antimicrob Chemother. 2009 Jun;63(6):1233–1243.
   Google Scholar
• Punyawudho B, Thammajaruk N, Ruxrungtham K, et al. Population pharmacokinetics and dose optimisation of ritonavir-boosted atazanavir in Thai HIV-infected patients. Int J Antimicrob Agents. 2017 Mar;49(3):327–332.
   Google Scholar
• Schipani A, Dickinson L, Boffito M, et al. Simultaneous population pharmacokinetic modelling of atazanavir and ritonavir in HIV-infected adults and assessment of different dose reduction strategies. J Acquir Immune Defic Syndr. 2013 Jan 1 62(1):60–66.
   Google Scholar
• Solas C, Gagnieu MC, Ravaux I, et al. Population pharmacokinetics of atazanavir in human immunodeficiency virus-infected patients. Ther Drug Monit. 2008 Dec;30(6):670–673.
   Google Scholar
• Kile DA, MaWhinney S, Aquilante CL, et al. A population pharmacokinetic-pharmacogenetic analysis of atazanavir. AIDS Res Hum Retroviruses. 2012 Oct;28(10):1227–1234.
   Google Scholar
• Foissac F, Blanche S, Dollfus C, et al. Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents. Br J Clin Pharmacol. 2011 Dec;72(6):940–947.
   Google Scholar
• COLCHICINE [product monograph] Pointe-Claire, Québec: Odan laboratories Ltd. 2016. [cited 2022 Mar 8]. Available from: https://pdf.hres.ca/dpd_pm/00034804.PDF
   Google Scholar
• Ferron GM, Rochdi M, Jusko WJ, et al. Oral absorption characteristics and pharmacokinetics of colchicine in healthy volunteers after single and multiple doses. J Clin Pharmacol. 1996 Oct;36(10):874–883.
   Google Scholar
• Rochdi M, Sabouraud A, Girre C, et al. Pharmacokinetics and absolute bioavailability of colchicine after i.v. and oral administration in healthy human volunteers and elderly subjects. Eur J Clin Pharmacol. 1994;46(4):351–354.
   Google Scholar
• Girre C, Thomas G, Scherrmann JM, et al. Model-independent pharmacokinetics of colchicine after oral administration to healthy volunteers. Fundam Clin Pharmacol. 1989;3(5):537–543.
   Google Scholar
• Kaddoura M, AlIbrahim M, Hijazi G, et al. COVID-19 therapeutic options under investigation. Front Pharmacol. 2020;11:1196.
   Google Scholar
• Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010 Apr;62(4):1060–1068.
   Google Scholar
• Paschke S, Weidner AF, Paust T, et al. Technical advance: inhibition of neutrophil chemotaxis by colchicine is modulated through viscoelastic properties of subcellular compartments. J Leukoc Biol. 2013 Nov;94(5):1091–1096.
   Google Scholar
• Schlesinger N, Firestein BL, Brunetti L. Colchicine in COVID-19: an old drug, new use. Curr Pharmacol Rep. 2020 Jul;18:1–9.
   Google Scholar