FAVIPIRAVIR (T-705) for Ebola Virus Disease: rational, dosage and outcome. Single-case experience.

Ramírez-Olivencia G, Borobia AM, Mora-Rillo M, de la Calle F, Arsuaga M, Lago M, Negredo A, Sánchez-Seco MP, Gonzalez del Valle L, Arnalich F, Carcas AJ, Arribas JR.
Hospital Universitario La Paz-Carlos III, Centro Nacional de Microbiología-ISCIII, Madrid. Spain marta.mora@salud.madrid.org

Objectives: Results:
The largest outbreak in the history of Ebola Virus Disease (EVD) is 44-year-old woman, diagnosed with EVD on date of illness (DOI) 8 with fever, malaise, hepatitis, diarrhoea and abdominal pain. After
currently ongoing. Favipiravir (FAVI), a new viral RNA polymerase inhibitor obtaining informed consent, patient started treatment with convalescent plasma (5 total 200cc-doses from two different EVD survivors).
already approved in Japan for the treatment of influenza, has in vitro activity On DOI-9 we administered two loading doses of 3000 mg of FAVI (50mg/kg) 12 hours apart. Third loading dose was not given due to
against other RNA viruses including Ebola (EBOV). FAVI has shown to be worsening abdominal pain. FAVI was restarted 24h later (1600mg TID, 25mg/kg TID) on DOI-11 without recurrence of abdominal pain.
effective in a mouse model of EVD while studies in non-human primates Due to stock-out, FAVI was interrupted for 16 hours on DOI-15. New loading dose (2400mg x 2 doses 8h-apart and 1600mg TID
models are still ongoing. We present a single-case description of high-dose afterwards) was started on DOI-16. FAVI was finally stopped on DOI-20 after two consecutive undetectable EBOV plasma viral loads
FAVI use in an EVD patient in Spain (VL). Two days after stopping FAVI, EBOV VL remained undetectable.

Potential adverse events:

Methods:
FAVI dose and administration schedule was selected considering -  Platelet count, normal on admission, decreased (37,000/mm3) on DOI 13 to 15. Thrombocytopenia could be attributed to EVD,
pharmacodynamic data in a mouse model and human volunteers Bemiparine (single dose), Piperacilin/Tazobactam, FAVI or Omeprazol. We discontinued Bemiparine and platelet count recovered. No
pharmacokinetic data, mainly: transfusions were required. No bleedings were observed.
-  No renal dysfunction was observed during admission, with daily creatinine under 1 mg/dL.
- EBOV-mouse model [Ostereich et al] showed EBOV-IC 90 17 μg/mL
-  Liver enzymes changes progressively normalized and appeared to be associated with EVD and not with FAVI therapy.
- therapeutic dose 300 mg/kg/day [Ostereich et al] .
- PK data in volunteers * with 1200/600 mg BID doses: -  EKG was not performed
-  Day 1. Cmax: 59.43 μg/mL,
-  Day 6. Cmax: 30.56 μg/mL, 10 IgG antibody titer Day of Illness ‐ 1:20,480
Plasma Viral
-  t1/2: 3,4-5,8 hr. RNA
9 ‐ 1:10,240
- No-observed-adverse-effect level in monkeys was 100 mg/kg/day *
- Plasma albumin binding was 53% * 8 ‐ 1:5,120

With this limited information, we aimed to maintain a free Cmin above IC90 7 IgM antibody titer ‐ 1:2,560
Log 10 Viral RNA (copies/mL)

(and as close as possible to 60 μg/mL of total concentration), with a loading

6 ‐ 1:1,280
dose of 50mg/kg BID and a maintenance dose of 25mg/kg TID

Titer
5 ‐ 1:640
FAVI was administered orally (200 mg tables) or in water suspension.
4 ‐ 1:320
New data come to scientific community since October 2014 when our
clinical decision was taken: 3 ‐ 1:160
The y axis on the left side of the graph shows the viral
-  Mentré et al offer similar loading and maintenance doses as we used in RNA load (solid lines). The horizontal dashed line indicates
November 2014
2 ‐ 1:80
the lower limit of detection of viral RNA.
-  Preliminary results of JIKI Trial (Efficacy phase II trial still ongoing in 1 ‐ 1:40 The y axis on the right side of the graph shows the
Guinea) had been present at CROI antibody titers.
0
Day of Illness 88 99 10
10 11
11 12
12 13
13 14
14 15
15 16
16 17
17 18
18 19
19 20
20 21
21 22
22 23
23
Daily total dosage of favipiravir (grey rectangles) is shown
References: mg_FAVI_day
Favipiravir mg /day 6000 0 3200 4800 4400 3600 0 4800 4800 4800 4800 1600 0 0 0 on the base of the graphic.
•  * data kindly provided by Company Dotted and stripped columns indicate transfusions of
•  Oestereich L et al. S. Antiviral Research. Antiviral Research 2014; 105:17–21
plasma from Donor #1 and #2
•  Mentré et al. The Lancet Infectious Diseases Published Online First: 27 November 2014.
doi:10.1016/S1473-3099(14)71047-3 Conclusion:
•  Sissoko D et al. Favipiravir in Patients with Ebola Virus Disease: Early Results of the JIKI
trial in Guinea | CROI Conference In our case a high dose of FAVI that could theoretically produce a free Cmin above
http://www.croiconference.org/sessions/favipiravir-patients-ebola-virus-disease-early-
results-jiki-trial-guinea
EBOV IC90 was well tolerated. FAVI is a potential therapeutic option for EVD patients .