key: cord-0808839-6dg6cb36 authors: Manosuthi, W.; Prasanchaimontri, I.-o.; Niyomnaitham, S.; Sirijatuphat, R.; Charoenpong, L.; Copeland, K.; Cressey, T. R.; Mokmued, P.; Chokephaibulkit, K. title: Pharmacokinetics of favipiravir in adults with mild COVID-19 in Thailand date: 2022-03-12 journal: nan DOI: 10.1101/2022.03.09.22271220 sha: a38124e0b10d36b5dd0fdfc0c6765bdb082e6472 doc_id: 808839 cord_uid: 6dg6cb36 We assessed the pharmacokinetics of favipiravir (FPV) in adults with symptomatic SARS-CoV-2 infection without pneumonia in Thailand. FPV dosing was 1800 mg twice-daily on day 1, then 800 mg twice-daily for 14 days. Eight subjects (7 female), median (range) age 39 (19-53) years and BMI 27.9 (18.0-33.6) were included. Inter-subject variability was high but all achieved minimum plasma concentrations (Cmin) above EC50 (9.7 mg/L). FPV was well tolerated; 1 subject stopped prematurely due to rash. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint Favipiravir (FPV) is a pyrazine carboxamide derivative that has recently been repurposed to treat mild-to-36 moderate cases of 2) . Preliminary studies have demonstrated its capacity to competitively 37 inhibit the replication of SARS-CoV-2 in-vitro (3-5) and possibly control viral progression, promote viral 38 clearance, as well as improve clinical outcomes in-vivo (5, 6). 39 40 FPV is a prodrug (T-705) that is intracellularly metabolised through ribosylation into its active form (T-41 705-RTP). Viral RNA-dependant RNA polymerase (RdRp) recognises this active form as a purine-base 42 analogue and incorporates it into nascent viral RNA whereby it exerts its antiviral activity (1, 2, 5-7). FPV 43 is primarily metabolised by hepatic aldehyde oxidase, and partially by xanthine oxidase, to a hydroxylated 44 inactive metabolite (T-705M1) that is excreted in the urine (4, 7, 8). 45 The recommended FPV dosing regimen for the treatment of COVID-19 in Thailand is 1800 mg twice-47 daily for the first day, and then 800 mg twice-daily for a total duration of 5-14 days (5). While numerous 48 studies have explored the clinical effects of such dosing regimens, few studies have assessed its 49 pharmacokinetics, and no studies have been performed in the Thai population (9, 10). It is important to 50 characterise the impact of regional and ethnic difference on the pharmacokinetic profile to ensure 51 optimised dosing for the viral variants circulating in the region (9). Our aim was to investigate the 52 pharmacokinetics of FPV in mild cases of COVID-19 without pneumonia within a Thai population. 53 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint Here we report the results of a pharmacokinetic sub-study of FPV nested within a prospective randomized 55 clinical trial of adults with symptomatic SARS-CoV-2 infection without pneumonia. Enrolled subjects 56 were randomised to receive supportive symptomatic care with or without FPV. The FPV dosing regimen 57 was 1800 mg twice-daily on the first day, and then 800 mg twice-daily for 5-14 days or until viral 58 clearance. Subjects receiving other medication with reported antiviral activity against SARS-CoV-2 were 59 excluded. Pharmacokinetic assessments were proposed to subjects receiving FPV. This study was 60 approved by the Siriraj Institutional Review Board (approval no. Si 434/2020) and registered at 61 Blood samples were drawn pre-dose, and 1-hour after FPV administration on days 1, 2, 3, 4, 5, 7, and 14. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint (9.7 mg/L) for all subjects, except for subject No. 6 after their first dose (8.6 mg/L). The C min and C max of 80 T-705 ranged from 12.1-132.2 mg/L and 14.5-201.2 mg/L, respectively, and was found to decreased 81 overtime. C min and C max of T-705M1 ranged from 1.6-6.7 mg/L and 2.0-24.8 mg/L, respectively, but 82 remained relatively stable overtime. Inter-subject variability was high, with a coefficient of variation 83 (CV) of 37-74% for T-705 and 12-62% for T-705M1. We would like to thank the National Centre for Global Health and Medicine, Japan and FUJIFILM 120 Toyama Chemical Co., Ltd. We are also thankful for the support from the National Institute of Health, 121 Thailand. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint None to declare 133 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint Population pharmacokinetics of favipiravir in patients with COVID 19 A review of the safety of favipiravir -a potential treatment 163 in the COVID-19 pandemic? Pharmacokinetics of Favipiravir in Critically Ill Patients With COVID 19 Favipiravir for the treatment of patients with 168 COVID-19: a systematic review and meta-analysis Department of Disease Control. Guidelines for clinical practice, diagnosis, treatment and prevention 170 of healthcare-associated infection in response to patients with COVID-19 infection Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 174 replication in vitro 2021. Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir COVID-19 Patients: An Exploratory Randomized, Controlled Trial Pharmacogenomics of COVID-19 179 therapies Pharmacokinetic modelling to estimate 181 intracellular favipiravir ribofuranosyl-5'-triphosphate exposure to support posology for is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 12, 2022. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22271220 doi: medRxiv preprint