Drug repurposing is a priority
The rapid spread of COVID-19 has triggered a global effort for accelerating the development of diagnostics, vaccines, and therapeutics. The threat of a possible recurring wave, as experienced with the 1918 Spanish flu pandemic , has added to the time pressure for identifying and offering therapeutic options. The anticipated 12 to 18 months timeframe required for making a vaccine available to patients , or the even longer time required for new drug development are challenged by the urgency of the situation. The repurposing of approved drugs and the acceleration of late-stage development compounds have therefore emerged as priority options for their ability to deliver solutions to patients faster.
Safety and drug-drug interaction (DDI) risks remain an issue.
Sanders et al. reviewed some candidate repurposed drugs and late-stage investigational drugs and their proposed mechanism of actions . Some therapeutic options are not without risks for clinical safety or DDIs. Hydroxychloroquine (HCQ), whether administered as a single agent or in combination with azithromycin, prolonged the QTc interval in COVID-19 patients [4, 5], and the QTc changes were greater when HCQ was co-administered with azithromycin (AZM) . The lopinavir/ritonavir (LPV/RTV) combination illustrated how complex the DDI may be, simultaneously involving CYP2D6 and P-gp inhibition and mixed CYP3A inhibition and induction [6, 7].
Leveraging quantitative clinical pharmacology
In their commentary, Rayner et al. advocated integration of clinical pharmacology in the evaluation of therapeutic options, e.g. optimizing the dosing in the overall patient population and in at-risk subpopulations, accounting for DDIs, and leveraging model-based quantitative analyses. Specifically, a freely-accessible interactive simulation tool has been designed to predict and graphically display the projected time-course of free drug concentrations at the site of action, e.g. the lungs, against in vitro IC50 target values . As of May 15th, 2020, simulations were available for AZM, chloroquine and HCQ, ivermectin, LPV/RTV, and tocilizumab.
In silico predictions with ivermectin suggested that a supra-therapeutic dose of 600 μg/kg administered orally for 3 consecutive days would result in peak concentrations in plasma and lung more than 9- and 21-fold below the target IC50 value, respectively, therefore jeopardizing the chance of being efficacious at a high dose . These simulations performed with an oral compound raised the issue of the potential therapeutic value of alternative routes of administration.
Hit early – Go local?
Based on a recent report, the nasopharyngeal viral load is high at early stages of the disease . Whether “early” means symptomatic, pauci-symptomatic, or asymptomatic has yet to be defined. Pharmacologically active concentrations could easily be attained by using topical formulations applied directly into the nasopharynx, yet minimizing systemic exposure and the associated safety and DDI risks. Subject to their availability, we hypothesize that topical formulations (e.g. intranasal and/or oral) could be valuable as an early therapeutic option in an attempt to reduce the nasopharyngeal viral load. This approach could limit the subsequent organ damage in the infected patient (e.g. pneumonia), and secondarily reduce the disease transmission rate. In addition, topical formulations would aid limiting the amount of active ingredient required per individual, therefore saving precious drug amounts for the general population.
Investigate and invest in topical formulations
We would like to invite stakeholders to invest in the development of topical formulations. While a local administration may be seen as a “rescue route” for compounds with a low probability of success by the oral route (e.g. ivermectin), we would probably benefit from a broader range of investigations. Several drug classes might be considered. For instance, drugs preventing the virus entry into the host cells (e.g. CQ and HCQ), RNA polymerase inhibitors (e.g. remdesivir, favipiravir), or direct-acting antiviral agents.
Hope needs Science
This blog is based on hope: hope that the above hypotheses make sense, and hope that some investigations may be successful. However, Hope is not Science and may not serve Science best. This is specifically why we need Science and scientists to make Hope materialize into therapeutic options.
- Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD) 1918 The influenza pandemic (H1N1). https://www.cdc.gov/flu/pandemic-resources/1918-pandemic-h1n1.html accessed 15th May 2020.
- CR Rayner, PF Smith, K Hershberger, D Wesche. Optimizing COVID-19 candidate therapeutics: Thinking Without Borders. Clin Transl Sci. 2020 Mar 25. doi: 10.1111/cts.12790.
- JM Sanders, ML Monogue, TZ Jodlowski, and JB Cutrell. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19). A Review. JAMA. doi:10.1001/jama.2020.6019
- F Bessière, H Roccia, A Delinière, R Charrière, P Chevalier, L Argaud, and M Cour. Assessment of QT Intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. Published online May 1, 2020. doi:10.1001/jamacardio.2020.1787
- NJ Mercuro, CF Yen, DJ Shim, TR Maher, CM McCoy, PJ Zimetbaum, and HS Gold. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. doi:10.1001/jamacardio.2020.1834
- C Wyen, U Fuhr, D Frank, RE Aarnoutse, T Klaassen, A Lazar, A Seeringer, O Doroshyenko, JC Kirchheiner, F Abdulrazik, N Schmeisser, C Lehmann, W Hein, E Schömig, DM Burger, G Fätkenheuer, and A Jetter. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. Clin Pharmacol Therap 2008, 84(1):75-82.
- D Mukherjee, J Zha, RM. Menon, and M Shebley. Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model. J Pharmacokin Pharmacodyn (2018) 45:443–456.
- https://www.covidpharmacology.com/in-silico-workbench/ accessed 15-May-2020.
- M Bray, C Rayner, F Noël, D Jans, and K Wagstaff. Ivermectin and COVID-19: a report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors’ responses, Antiviral Research, https://doi.org/10.1016/j.antiviral.2020.104805.
- FX Lescure, L Bouadma, D Nguyen, M Parisey, PH Wicky, S Behillil, A Gaymard, M Bouscambert-Duchamp, F Donati, Q Le Hingrat, V Enouf, N Houhou-Fidouh, M Valette, A Mailles, JC Lucet, F Mentre, X Duval, D Descamps, D Malvy, JF Timsit, B Lina, S van-der-Werf, and Y Yazdanpanah. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis. 2020 Mar 27. doi: 10.1016/S1473-3099(20)30200-0.
To learn more about how quantitative clinical pharmacology is advancing therapeutics for COVID-19, please watch this webinar: