key: cord-343093-qjg5az3d
authors: Irie, Kei; Nakagawa, Atsushi; Fujita, Hirotoshi; Tamura, Ryo; Eto, Masaaki; Ikesue, Hiroaki; Muroi, Nobuyuki; Tomii, Keisuke; Hashida, Tohru
title: Pharmacokinetics of Favipiravir in Critically Ill Patients with COVID‐19
date: 2020-05-31
journal: Clin Transl Sci
DOI: 10.1111/cts.12827
sha: 
doc_id: 343093
cord_uid: qjg5az3d

Since December 2019, a novel coronavirus (SARS‐CoV‐2) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID‐19). The anti‐retroviral drug favipiravir (FPV) has been experimentally used for COVID‐19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high‐performance liquid chromatography in patients with severe COVID‐19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1600 mg of FPV twice daily on Day 1, followed by 600 mg twice daily from Day 2 to Day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty‐nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8–12 h) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and EC(50) (9.7 µg/mL) against SARS‐CoV‐2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID‐19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that is closely related to bat-derived SARS-like coronaviruses (1) .

Since its outbreak in Wuhan, China in December 2019, the virus has rapidly spread worldwide and caused the respiratory illness, coronavirus disease 2019 (COVID-19) (2) . The symptoms of COVID-19 are generally mild; however, 6.1-14.2% of the patients, especially the elderly or those with complications, developed severe symptoms requiring admission to intensive care units (ICU) and mechanical ventilation. Worsening of these symptoms resulted in death in 1.4-9.7% of

This article is protected by copyright. All rights reserved patients with COVID-19 (3, 4) . On April 28, 2020, approximately 211,000 people died of COVID-19 worldwide (5). In spite of ongoing clinical trials for combating COVID-19 with existing drugs (lopinavir/ritonavir, remdesivir, ciclesonide, chloroquine, and tocilizumab) and vaccines (mRNA-1237 and INO-4800), no specific treatment exists at this point.

In Japan, favipiravir (FPV) has been experimentally used for treating COVID-19 since March 2020. FPV is an RNA-dependent RNA polymerase (RdRp) inhibitor acting on a broad spectrum of various viral RNA polymerases (6, 7). The drug was originally developed for resistant influenza virus infections. The use of FPV is restricted and it cannot be used without state permission in Japan (8, 9) . Not only is there no precedent for treatment of COVID-19 with FPV, but its clinical use has also been highly limited until now.

Pharmacokinetics (PK) study of FPV in healthy subjects and few influenza patients was conducted during drug development (9). However, little is known about the PK of FPV in critically ill patients admitted to ICUs and requiring invasive oxygenation. In ICU patients, PK is dramatically changed owing to increased cardiac output, capillary leak, renal and hepatic clearance, and altered protein binding properties (10).

The PK study of FPV in critically ill patients would support the efficacy and safety of the drug for treating COVID-19. Therefore, in this study, we evaluated the PK of FPV in patients with COVID-19 who were admitted to the ICU and placed on mechanical ventilation.

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Critically ill patients with COVID-19 who were admitted to the ICU on mechanical ventilation and administered FPV tablets (AVIGAN ® tablet 200 mg, Toyama Chemical Co., Ltd., Tokyo, Japan) between May 19, 2020 and April 16, 2020 in Kobe City Medical Center General Hospital were eligible for this observational study. FPV was not approved for treatment of COVID-19 in Japan, and the efficacy and dosage were not established. Therefore, FPV was administered on a compassionate-use basis to the patients included in this study. Demographic and clinical characteristics including age, gender, body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine (SCr), comorbidities, other drugs for COVID-19, co-medications, possible adverse drug reactions of FPV, and clinical status after starting FPV treatment were investigated. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Kobe City Medical Center General Hospital (Approval number: Zn200418, Approval date: March 31, 2020). All study participants or their families provided informed consent.

According to the dosage indicated for influenza, patients were administered 1600 mg of FPV twice on Day 1, followed by 600 mg twice daily from Day 2 to Day 5 (or more if needed).

Patients on mechanical ventilation while in the ICU were administered suspensions of FPV tablets through nasogastric tube. The suspensions were prepared by dissolving FPV tablets in water at 55°C. The administration procedure was followed as instructed by the manufacturer and stability was confirmed.

This article is protected by copyright. All rights reserved Blood samples (serum) were obtained daily from the patients. The times when FPV was administered and blood samples were obtained were recorded. The serum samples were stored at -20℃ until measurement and handled only when wearing personal protective equipment.

Bulk powder of FPV were purchased from Selleck Chemicals (Houston, TX, USA).

Serum concentrations of FPV were measured by Agilent 1200 high performance liquid chromatography (HPLC) system (Agilent, Waldbronn, Germany). The linear calibration range of FPV was 1-100 µg/mL (R 2 > 0.999), and the lower limit of quantification (LLOQ) was 1 µg/mL.

The intra-assay accuracy (relative error %, n = 5) and precision (relative standard deviation %, n = 5) were 1.9-4.9% and 90.1%-96.4%, respectively. The inter-assay accuracy and precision (n = 3) were 0.3-1.4% and 95.1%-100.5%, respectively. FPV was stable in serum at 25°C for 48 h and at -20°C for 7 days.

The clinical status after starting FPV was evaluated on Day 1-5, Day 7, and Day 14 by a seven-category ordinal scale as follows:

1 Non-hospitalization, No limitation of activities 2 Non-hospitalization, limitation of activities 3 Hospitalization, not-required oxygen 4 Hospitalization, required oxygen by mask or nasal prongs 5 Hospitalization, required non-invasive ventilation and/or high-flow oxygen 6 Hospitalization, required oxygen (invasive) and/or extracorporeal membrane oxygenation

This article is protected by copyright. All rights reserved (ECMO) 7 Death Body temperature and PaO 2 /FiO 2 were also studied each day. PaO 2 /FiO 2 was defined as the ratio of the partial pressure of arterial oxygen to the percentage of inspired oxygen.

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Seven patients were included in this observational study. Their baseline characteristics before FPV initiation are summarized in Table 1 . All the patients were diagnosed with COVID-19 using real-time polymerase chain reaction (RT-PCR)-tested nasopharyngeal swabs and radiography imaging. Median (range) days from COVID-19 diagnosis, hospitalization, and admission to ICU up to FPV initiation were 6 days (0 to 10), 2 days (0 to 9), and 1 day (-1 to 9), respectively. Five patients were admitted to the ICU and placed on mechanical ventilation before treatment with FPV. Two patients (4 and 5) were orally administered FPV (1600 mg) twice and then admitted to the ICU for intubation. Patients placed on mechanical ventilation were administered FPV through nasogastric tube and Patient 1 continued to receive FPV through nasogastric tube even after extubation. Patients 1 and 6 were administered FPV for 7 and 10 days, respectively, whereas the other patients were administered FPV for 5 days. The patients were administered many drugs including antibiotics, opioids, analgesics, sedatives, and pressors during FPV treatment, but medications known to interact with FPV were avoided.

Forty-nine samples were obtained from eligible patients to evaluate FPV concentrations.

All FPV concentrations and the corresponding blood sampling time after FPV administration are summarized in Table 2 . For example, the concentration after 8 h from the first 1600 mg dosing was "< 1.0" in Patient 1. Most sample concentrations were lower than the LLOQ (1 µg/mL) and EC 50 (9.7 µg/mL) against SARS-CoV-2 tested in vitro (11). Patients 4 and 5 presented remarkably high FPV concentrations before intubation on the first day, which then declined after intubation. Patient 1 was weaned from mechanical ventilation from Day 5 onwards, and the FPV concentration slightly increased on Day 7 (2.7 µg/mL).

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The best score of clinical status, highest body temperature, and lowest PaO 2 /FiO 2 on each day after FPV administration are shown in Table 1 . One out of seven patients (14.3%) showed improvement and was weaned from mechanical ventilation 7 days after starting FPV. In addition, three out of seven patients (42.9%) improved and was weaned from mechanical ventilation after 14 days and two patients (28.6%) did not require oxygenation after 14 days. Mild AST increase was observed in Patient 5 as an adverse event related to FPV, but multiple other drugs were suspected to cause this event.

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In the present study, we evaluated FPV serum concentrations in critically ill patients with COVID-19 who were admitted to the ICU and required mechanical ventilation. The concentration was much lower than that previously reported in healthy subjects.

According to the PK study (Day 1: 1600 mg BID, Day 2-5: 600 mg BID) in AVIGAN ® package insert, FPV trough (after 12 h) concentration in healthy subjects was 20-60 µg/mL (8, 9).

However, the trough concentrations (within 8-12 h) in patients receiving the same regimen in this study were mostly lower than the LLOQ. This underexposure to FPV in severely ill patients with COVID-19 is of great concern as the EC 50 (9.7 µg/mL) against SARS-CoV-2 tested in vitro (11) is reportedly much higher than that against influenza virus (9). Two patients who were intubated after taking FPV orally had higher FPV concentrations than the other patients who were intubated with FPV. These observations suggest that exposure to FPV is different depending on the severity of illness which is usually high in ICU-requiring patients.

A PK case study of FPV in patients with severe influenza needing continuous venovenous hemofiltration was reported. In the study, FPV was administered at 400 mg BID and the C max was only 4.43 µg/mL indicating increased distribution volume and clearance (12). PK of FPV was also studied in Ebola virus disease (JIKI study). In the JIKI study, FPV was used at doublet dosage Many studies report increased drug distribution volume (14, 15) and increased clearance

This article is protected by copyright. All rights reserved (16, 17) in ICU patients. In addition, gastrointestinal absorption might be decreased by the use of drugs such as sedatives and opioids, which reduce gastrointestinal motility. Previous studies on oral drug formulations report decreased concentration when administered through nasogastric tube in critically ill patients (18, 19) . Therefore, FPV PK in ICU patients can be quite different from that in healthy volunteers. Unlike general septic shock, patients with severe COVID-19 present acute respiratory distress syndrome (ARDS) pathology and need deep sedation and conservative fluid management to prevent lung injury (20, 21). Although the reason could not be confirmed because peak time-point concentrations were not obtained, decreased drug absorption might be of greater concern here. In addition, the suspension of FPV tablets showed stability, but the bioavailability has not been confirmed. The administration procedure of FPV tablets slurry requires further examination. Furthermore, FPV is mainly metabolized by aldehyde oxidase (AO) and exhibits non-linear PK. The trough concentration of FPV seems to increase with dose and time-dependent "self-inhibition of AO" (9, 22). Many AO substrates report poor PK with rapid metabolism and failed drug development (23-25). Therefore, the self-inhibition of AO is speculated to be necessary to maintain significant FPV concentration. 

This article is protected by copyright. All rights reserved possible). Otherwise, we might underestimate the efficacy of the limited drugs that show promise as a treatment for COVID-19. This problem should be revived in the influenza pandemics again.

In conclusion, FPV concentrations in critically ill patients were much lower than that in healthy volunteers, which is of great concern during treatment. Further study is required to determine the optimal strategy for treatment of patients with severe COVID-19.

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Little is known about the PK of FPV in critically ill patients with COVID-19 admitted to ICUs and requiring invasive oxygenation as the clinical use of FPV has been limited and has no precedent in treating COVID-19.

The pharmacokinetics of FPV was evaluated in patients with severe COVID-19 to reveal the clinical outcomes.

FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial.

It may help with planning the FPV clinical trial for critically ill patients with COVID-19 with regard to the optimal dosage and formulation.

COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 395, 1054-1062 (2020). 

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This article is protected by copyright. All rights reserved 

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

COVID-19 pandemic: perspectives on an unfolding crisis

Clinical course and risk factors for mortality of adult inpatients with

We thank all the patients who participated in this study and their families, the individuals who expedited rapid approval from the Ethics Committee and collection of blood samples, and the medical staff on the frontlines of treating COVID-19 in Kobe City Medical Center General Hospital.

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