Favipiravir

Corona virus is a pandemic disease. It is a kind of respiratory disease. This infection is now rapidly increasing day by day. Favipiravir is an antiretroviral drug that is used to treat covid-19. This treatment started in March 2020 in Japan. Toyama Chemical Company Limited has first introduced Favipiravir as Avigan tablet. It is a pyrazine carboxamide derivative compound whose chemical formula is 6‐fluoro‐3‐hydroxy‐2‐pyrazine carboxamide. Though, the main pharmacokinetics of Favipiravir is still unknown in critical covid 19 patients. Favipiravir is given 1600 mg twice daily on the first day to covid 19 patients. From the next day about 2-5 days, Favipiravir is given 600 mg twice daily. In Bangladesh, Beacon pharma first launched Favipiravir from Japan which brand name is also Favipiravir. It shows a 96% success rate in the clinical trial. Each tablet cost about 400 takas. Favipiravir is basically an RNA-dependent RNA polymerase inhibitor that acting on a broad spectrum of viral RNA polymerases. When Favipiravir was first introduced for the treatment of influenza virus infection. The pharmacokinetics of Favipiravir in a healthy person and a new influenza patient was conducted during drug development. In ICU patients, PKs are dramatically changed by increasing cardiac output, capillary leak, and hepatic clearance. It is an efficacy and safe treatment to cure covid 19 patients.

 

Administration of Favipiravir:

As we know, Favipiravir was used to treatment against influenza virus. Favipiravir is a synthetic prodrug that has anti-viral activity. The infected patient was administered about 16 mg of Favipiravir twice a day. In the next two to five days, it administered 600 mg twice a day. For ICU patients, suspension of tablet is given by nasogastric tubes. The suspension is made by adding water at 55 °C.

 

Pharmacokinetic Sampling:

The serum was daily collected from patients, who were administered Favipiravir. These serum samples were stored under -20 °C for further pharmacokinetic study purposes. This sampling was handled with proper equipment.

 

Pharmacokinetic Measurement:

Serum concentration of Favipiravir was measured by HPLC (High-Performance Liquid Chromatography). The linear calibration range of Favipiravir is 1-100 μg/mL and LLOQ was 1 μg/Ml. Moreover, Favipiravir was stable in serum at 25 °C for 48 hours and 20 °C for 7 days.

 

Clinical Status After Starting Favipiravir:

There are some categories to detect clinical status after starting Favipiravir. The interval is about day 1, day 2-5, day 7, and day 14. Body temperature is also studied. PaO2/FiO2 were also studied.

1. The first one is about those patients who are non-hospitalized and no limitation of activities.

2. Patients are non-hospitalized and limited in their daily activities.

3. Patients are hospitalized but not-required oxygen.

4. Patients are hospitalized and required oxygen by mask or nasal prongs.

5. Hospitalized and required noninvasive ventilation or high-flow oxygen.

6. Patients are hospitalized and required oxygen and extracorporeal membrane oxygenation.

7. Death of patients.

 

Mechanism of Favipiravir:

                                                              Image: Mechanism of Favipiravir

1. In tissue, Favipiravir’s molecule undergoes the phosphorylation of Favipiravir-RTP (Replication terminator protein). It is the active form of Favipiravir.

2. The molecule of Favipiravir acts as a substrate for the RNA-dependent RNA-polymerase enzyme. So, the main activity is to terminate viral protein synthesis.

3. This portion is now incorporated with a viral RNA strand that prevents further extension. This mechanism of action, along with the preservation of the catalytic domain of the RNA-dependent RNA-polymerase enzyme across different kinds of RNA viruses. It can explain the broad spectrum of activity of Favipiravir.

4. Recently, in vitro study shows that Favipiravir induces lethal mutagenesis for the influenza virus and makes it a virucidal drug. A similar activity is also shown against the SARS-CoV-2 virus.

 

Pharmacokinetics of Favipiravir:

Favipiravir is an antiviral drug that is derived by chemical modification of the pyrazine moiety (T-1105). In ill patients, the maximum plasma concentration of Favipiravir occurred at only two hours. The half time of Favipiravir is 2.5-5 hours. About 54% of Favipiravir is bind to plasma protein. This portion of Favipiravir is bound to human serum albumin (65%) and α1‐acid glycoprotein (6.5%). The remaining portion of the drug undergoes liver metabolism. They produced oxidative metabolite as a byproduct and then excreted by the kidney. The active metabolite compound is T‐705‐RTP. In mice, excretion of Favipiravir by the liver occurs rapidly. A clinical study was obtained from 66 patients who were under treatment with Favipiravir. On day 2, drug concentration in blood plasma was 46.1 µg/mL but on day 4, drug concentration in blood plasma was 25.9 µg/mL. It means that, if any patient takes Favipiravir regularly, drug concentration will decrease day by day.

 

Favipiravir’s Dosing Regimen in Covid‐19:

This is the most critical stage for antiviral therapy or drug. The approved regimen of Favipiravir is 1600mg for the first day and 600 mg for next 2^nd-5^th day (twice a day). For critical patients, sometimes Favipiravir is given 1800mg for the first day and 800 mg for the next 2^nd-5^th day (twice a day). This is a safety range that is clinically proved. A 6,000 mg (2,400 mg, 2,400 mg, and 1,200 mg- thrice a day) loading dose on day 1 followed by a 2,400 mg maintenance dose (1,200 mg- twice a day) on day 2 to day 9 was well tolerated. The mean steady‐state trough concentration was 46.1 µg/mL on day 2 and fell to 25.9 µg/mL on day 4. Both of these drug concentrations were significantly lower than the predicted targeted concentrations of 54.3 µg/mL and 64.4 µg/mL, respectively.

 

Potential Drug-Drug Interaction In Pharmacokinetics:

Different types of drugs are unavoidable in the treatment of COVID-19 especially for those patients who are suffered from diabetes, hypertension, arrhythmia, cardiovascular disease, kidney injury. Generally, Favipiravir is metabolized in liver Aldehyde Oxidase in the cytosol. The active metabolite compound is T‐705‐RTP. In past, some healthy volunteers tested that concomitant administration of Favipiravir increased the AUC of acetaminophen and acetaminophen glucuronide by 20% and 23–34%, respectively, Again, the AUC of acetaminophen sulfate decreased by 29–35%, and the excretion of acetaminophen and the acetaminophen glucuronide increased in urine. Co‐incubation of Favipiravir with human liver S9 inhibits acetaminophen sulfate formation with an Inhibitory concentration (IC₅₀) value of 24 µg/mL that suggesting inhibition of the sulfate transferase enzyme.  When combined with Favipiravir, the recommended maximum daily doses of acetaminophen will be 3 grams per day. In the case of in vitro study, there is some selective estrogen receptor such as estradiol, tamoxifen, the H2 receptor such as cimetidine are potent aldehyde oxidase inhibitors. Moreover, clinically Drug-drug- interaction is based on aldehyde oxidase inhibition which is yet to be established between cimetidine and zaleplon. Again, some drugs such as famciclovir, zaleplon are also metabolized by aldehyde oxidase.

 

Favipiravir is an antiviral drug that can treat as a substitute for compassionate use in COVID‐19. Their main mechanism is the inhibiting of RNA dependent RNA polymerase of a virus. Favipiravir was first introduced to treat against influenza virus. The safety data and previous case studies are analyzed again to treat COVID-19 patients. The efficacy of Favipiravir to COVID-19 patients is not exact efficacy. All data are collected by the clinical trial. The exact efficacy of Favipiravir paused for further clinical confirmation from FDA. There are some side effects of Favipiravir such as mild elevation of transaminase, asymptomatic hyperuricemia. In the Indian trail, a specific adverse effect is not shown. It is teratogenic, so we should not give Favipiravir to pregnant women. But in this pandemic situation, Favipiravir is a valuable drug to treat COVID-19 patients.

 

Reference:

1. Kei Irie1,2, Atsushi Nakagawa3, Hirotoshi Fujita1, Ryo Tamura1, Masaaki Eto4, Hiroaki Ikesue1, Nobuyuki Muroi1, Keisuke Tomii3 and Tohru Hashida1, Pharmacokinetics of Favipiravir in Critically Ill Patients with COVID-19.

2. UmangAgrawalaReymaRajubZarir F.Udwadiac, October, 2020, Favipiravir: A new and emerging antiviral option in COVID-19.

3. Report on the Deliberation Results Avigan Tablet 200 mg by Pharmaceuticals and Medical Devices Agency (PMDA), March 4, 2014. Accessed April 25, 2020.

4. Yin‐Xiao Du, Xiao‐Ping Chen, 4^th April, 2020, Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019‐nCoV Infection.

5. Madelain, V. et al. Ebola virus infection: review of the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials. Clin. Pharmacokinet. 55, 907–923 (2016).

6. Bocan, T.M. et al. Synthesis of [(18) F] Favipiravir and biodistribution in C3H/HeN mice as assessed by positron emission tomography. Sci. Rep. 9, 1785 (2019).

7. Nguyen, T.H. et al. Favipiravir pharmacokinetics in Ebola‐Infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl. Trop. Dis. 11, e0005389 (2017).

8. Wang, Y. et al. Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. J. Infect. Dis. 

9. Zhao, Y. et al. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. Br. J. Clin. Pharmacol. 80, 1076–1085 (2015).

10. T. Baranovich, S.S. Wong, J. Armstrong, et al.705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro J Virol, 87 (2013), pp. 3741-3751.