PIRFENIDONE FOR CORONAVIRUS TREATMENT
Provided herein are methods and uses involving pirfenidone pharmaceutical compositions (e.g., extended-release pirfenidone pills (e.g., tablets)) in treating COVID-19, treating and/or preventing viremia and/or viremia-induced disease caused by a virus, and/or an infection with a virus (e.g., DNA virus, RNA virus, for example, coronavirus (e.g., severe acute respiratory syndrome coronavims-2 (SARS-CoV-2) and variants thereof, severe acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV)), in a subject (e.g., subject with COVID-19). Provided are methods of reducing elevated levels of one or more markers of inflammation (e.g., CRP, ferritin, LDH), inhibiting an inflammatory response (e.g., virus-induced) and/or inhibiting a cascade by one or more pro-inflammatory cytokines (e.g., TNF-α, IEN-γ, IL-Iβ, IL-6, IL-12) and/or in a subject (e.g., a subject with COVID-19 optionally having liver contraindications for pirfenidone).
1 . A method of treating or preventing viremia caused by a virus in a subject in need thereof, the method comprising administering pirfenidone to the subject.
2 . A method of treating or preventing viremia-induced disease in a subject in need thereof, the method comprising administering pirfenidone to the subject.
3 . A method of treating COVID-19 and/or COVID-19 disease caused by a SARS-CoV-2 variant thereof in a subject in need thereof, the method comprising administering pirfenidone to the subject.
4 . A method of treating or preventing an infection with a virus in a subject in need thereof, the method comprising administering pirfenidone to the subject.
5 . A method of inhibiting an inflammatory response by one or more pro-inflammatory cytokines in a subject in need thereof, the method comprising administering pirfenidone to the subject.
6 . A method of inhibiting a cascade by one or more pro-inflammatory cytokines in a subject in need thereof, the method comprising administering pirfenidone to the subject.
7 . A method of reducing elevated levels of one or more markers of inflammation in a subject in need thereof with viremia caused by a virus, the method comprising administering pirfenidone to the subject.
8 . The method of any one of claims 1 - 7 , wherein the pirfenidone is formulated in one or more extended-release pills, wherein each of the one or more extended-release pills comprises the pirfenidone and one or more excipients.
9 . The method of any one of claims 1 - 8 , wherein each of the one or more extended-release pills comprises approximately 100 mg to approximately 850 mg of pirfenidone.
10 . The method of any one of claims 1 - 9 , wherein each of the one or more extended-release pills comprises approximately 600 mg of pirfenidone.
11 . The method of any one of claims 1 - 10 , wherein a C max from a first dose of the one or more extended-release pills is between approximately 1.0 μg/mL to 10.0 μg/mL.
12 . The method of any one of claims 1 - 11 , wherein the C max from a first dose of the one or more extended-release pills is between approximately 1.0 μg/mL to 4.0 μg/mL.
13 . The method of any one of claims 1 - 7 , wherein the pirfenidone is formulated in one or more sustained-release pills, wherein each of the one or more sustained-release pills comprises the pirfenidone and one or more excipients.
14 . The method of any one of claims 1 - 8 or 13 , wherein each of the one or more sustained-release pills comprises approximately 100 mg to approximately 850 mg of pirfenidone.
15 . The method of any one of claims 1 - 9 or 14 , wherein each of the one or more sustained-release pills comprises approximately 600 mg of pirfenidone.
16 . The method of any one of claims 1 - 10 or 15 , wherein a C max from a first dose of the one or more sustained-release pills is between approximately 1.0 μg/mL to 10.0 μg/mL.
17 . The method of any one of claims 1 - 11 or 16 , wherein the C max from a first dose of the one or more sustained-release pills is between approximately 1.0 μg/mL to 4.0 μg/mL.
18 . The method of any one of claims 1 - 17 , wherein a T max is between approximately 1.5 hours to 8.0 hours.
19 . The method of any one of claims 1 - 18 , wherein the T max is between approximately 3.0 hours to approximately 5.0 hours.
20 . The method of any one of claims 1 - 19 , wherein an AUC 0-t is between approximately 10.0 μg*hours/mL to approximately 30.0 μg*hours/mL.
21 . The method of any one of claims 1 - 20 , wherein the half-life (T 1/2 ) is between approximately 1.6 hours to approximately 8.0 hours.
22 . The method of any one of claims 7 - 21 , wherein the one or more excipients comprise one or more excipients selected from the group consisting of a compression binder, diluent, disintegrant, coating agent, rate-controlling polymer, anti-caking agent, adsorbent, lubricant, and glidant.
23 . The method of any one of claims 7 - 22 , wherein at least one excipient of the one or more excipients is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), microcrystalline cellulose, silicon dioxide, and sodium stearyl fumarate.
24 . The method of any one of claims 7 - 23 , wherein each of the one or more sustained-release pills comprises:
a) approximately 100 mg to approximately 850 mg of pirfenidone;
b) microcrystalline cellulose;
c) low viscosity HPMC;
d) high viscosity HPMC;
e) silicon dioxide; and
f) sodium stearyl fumarate.
25 . The method of any one of claims 7 - 23 , wherein each of the one or more extended-release pills comprises:
a) approximately 100 mg to approximately 850 mg of pirfenidone;
b) microcrystalline cellulose;
c) low viscosity HPMC;
d) high viscosity HPMC;
e) silicon dioxide; and
f) sodium stearyl fumarate.
26 . The method of any one of claims 7 - 23 or 25 , wherein each of the one or more extended-release pills comprises:
a) approximately 100 mg to approximately 850 mg of pirfenidone;
b) approximately 100 mg to 125 mg microcrystalline cellulose;
c) approximately 50.0 mg to 100.0 mg low viscosity HPMC;
d) approximately 30.0 mg to 50.0 mg high viscosity HPMC;
e) approximately 5.0 mg to 10.0 mg silicon dioxide; and
f) approximately 5.0 mg to 10.0 mg sodium stearyl fumarate.
27 . The method of any one of claims 1 - 24 , wherein the one or more sustained-release pills are formulated as tablets, capsules, or gel capsules.
28 . The method of any one of claims 1 - 23 or 25 - 27 , wherein the one or more extended-release pills are formulated as tablets, capsules, or gel capsules.
29 . The method of any one of claims 1 - 23 or 25 - 28 , wherein the one or more extended-release pills are formulated as tablets.
30 . The method of any one of claims 1 , 2 , or 7 - 29 , wherein the viremia is selected from the group consisting of primary viremia, secondary viremia, active viremia, and passive viremia.
31 . The method of any one of claims 1 , 2 , or 7 - 30 , wherein the viremia caused by the virus is viremia caused by an RNA virus or a DNA virus.
32 . The method of any one of claims 2 or 7 - 31 , wherein the viremia-induced disease is caused by an infection with a virus.
33 . The method of any one of claims 5 or 8 - 32 , wherein the inflammatory response is induced by an infection with a virus.
34 . The method of any one of claims 4 or 8 - 33 , wherein the infection with the virus is infection with an RNA virus or a DNA virus.
35 . The method of claim 34 , wherein the viremia caused by an RNA virus is viremia caused by a coronavirus.
36 . The method of claim 34 or 35 , wherein the infection with the RNA virus is an infection with a coronavirus.
37 . The method of any one of claims 34 - 36 , wherein the coronavirus is severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
38 . The method of any one of claims 34 - 36 , wherein the coronavirus is a SARS-CoV-2 variant of B.1.1.7, B.1.351, B.1.525, B.1.526, P.1, B.1.427, B.1.429, and/or SARS-CoV-2 variants with the Q677P and/or L452R mutations.
39 . The method of any one of claims 34 - 38 , wherein the coronavirus causes coronavirus disease 2019 (COVID-19).
40 . The method of any one of claims 34 - 38 , wherein the coronavirus is severe acute respiratory syndrome-associated coronavirus (SARS-CoV).
41 . The method of any one of claims 34 - 38 , wherein the coronavirus is Middle East respiratory syndrome coronavirus (MERS-CoV).
42 . The method of any one of claims 1 - 41 , wherein the subject develops fibrosis.
43 . The method of any one of claims 1 - 42 , wherein the fibrosis is lung fibrosis or liver fibrosis.
44 . The method of any one of claims 1 - 43 , wherein the subject has one or more contraindications for standard immediate-release pirfenidone.
45 . The method of any one of claims 1 - 44 , wherein the subject has liver disease, liver damage, or a liver injury.
46 . The method of any one of claims 1 - 45 , wherein the subject has liver disease with a Pugh-Child score of class A, class B, or class C.
47 . The method of any one of claims 45 or 46 , wherein the liver disease is chronic liver disease.
48 . The method of any one of claims 1 - 47 , wherein the pirfenidone is formulated in one or more extended-release tablets, the subject has one or more liver contraindications for standard-release pirfenidone; and each of the one or more extended-release tablets comprises:
a) approximately 100 mg to approximately 850 mg of pirfenidone;
b) approximately 100 mg to 125 mg microcrystalline cellulose;
c) approximately 50.0 mg to 100.0 mg low viscosity HPMC;
d) approximately 30.0 mg to 50.0 mg high viscosity HPMC;
e) approximately 5.0 mg to 10.0 mg silicon dioxide; and
f) approximately 5.0 mg to 10.0 mg sodium stearyl fumarate.
49 . The method of any one of claims 1 - 48 , comprising blocking and/or reducing an inflammatory response.
50 . The method of any one of claims 1 - 49 , comprising inhibiting the inflammatory response by one or more pro-inflammatory cytokines.
51 . The method of any one of claims 1 - 50 , wherein the inflammatory response is a cascade by the one or more pro-inflammatory cytokines.
52 . The method of any one of claims 1 - 51 , wherein the inflammatory response results in acute respiratory distress syndrome (ARDS).
53 . The method of any one of claims 1 - 52 , wherein the subject has elevated levels of one or more markers of inflammation.
54 . The method of claim 53 , wherein the one or more markers of inflammation are selected from the group consisting of D-dimers, C-reactive protein (CRP), ferritin, and lactic acid dehydrogenase (LDH).
55 . The method of any one of claims 1 - 54 , wherein the one or more markers of inflammation comprise C-reactive protein (CRP), ferritin, and lactic acid dehydrogenase (LDH).
56 . The method of any one of claims 1 - 55 , wherein the subject has elevated levels of one or more pro-inflammatory cytokines.
57 . The method of claim 56 , wherein the one or more pro-inflammatory cytokines are selected from the group consisting of TNF-α, IFN-γ, IL-1β, IL-6, and/or IL-12.
58 . The method of any one of claims 1 - 57 , wherein the subject has high viral burden and elevated levels of one or more markers of inflammation.
59 . The method of any one of claims 1 - 58 , wherein the subject that has high viral burden has low levels of cycle threshold (Ct).
60 . The method of any one of claims 1 - 59 , wherein the subject has pneumonia.
61 . The method of any one of claims 1 - 60 , wherein the subject has lung inflammation and/or lung fibrosis.
62 . The method of any one of claims 1 - 61 , wherein the subject has acute respiratory distress syndrome (ARDS).
63 . The method of any one of claims 1 - 62 , wherein the subject has COVID-19.
64 . The method of any one of claims 1 - 63 , wherein the pirfenidone is formulated in one or more extended-release pills, wherein each of the one or more extended-release pills comprises the pirfenidone and one or more excipients; the coronavirus is severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and/or a SARS-CoV-2 variant thereof; and the subject has coronavirus disease 2019 (COVID-19) and/or a disease caused by a SARS-CoV-2 variant thereof.
65 . The method of any one of claims 1 - 63 , wherein the pirfenidone is formulated in one or more sustained-release pills, wherein each of the one or more sustained-release pills comprises the pirfenidone and one or more excipients; the coronavirus is severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); and the subject has coronavirus disease 2019 (COVID-19).
66 . The method of any one of claims 1 - 65 , wherein the subject has one or more contraindications for immediate-release pirfenidone.
67 . The method of any one of claims 1 - 65 , wherein the subject has one or more contraindications for standard-release pirfenidone.
68 . The method of any one of claims 1 - 67 , wherein a daily dosage comprises approximately 400 mg to approximately 4800 mg of pirfenidone per day.
69 . The method of any one of claims 1 - 68 , wherein a daily dosage comprises approximately 800 mg to approximately 3000 mg of pirfenidone per day.
70 . The method of any one of claims 1 - 69 , wherein a daily dosage comprises approximately 1000 mg to approximately 2400 mg of pirfenidone per day.
71 . The method of any one of claims 1 - 70 , wherein the one or more sustained-release tablets are administered orally 1 to 8 times per day.
72 . The method of any one of claims 1 - 71 , wherein the one or more sustained-release pills are administered orally two times per day.
73 . The method of any one of claims 1 - 72 , wherein the one or more sustained-release pills are administered for approximately ten days or more.
74 . The method of any one of claims 1 - 70 , wherein the one or more extended-release tablets are administered orally 1 to 8 times per day.
75 . The method of any one of claims 1 - 70 or 74 , wherein the one or more extended-release pills are administered orally two times per day.
76 . The method of any one of claims 1 - 70 or 75 , wherein the one or more extended-release pills are administered for approximately ten days or more.
77 . The method of any one of claims 1 - 70 or 74 - 76 , wherein the one or more extended-release pills are administered for approximately fourteen days or more.
78 . The method of any one of claims 1 - 70 or 74 - 76 , wherein the one or more extended-release pills are administered for approximately twenty-eight days or more.
79 . The method of any one of claims 1 - 73 , wherein the one or more sustained-release pills are administered for approximately thirty days or more.
80 . The method of any one of claims 1 - 73 or 79 , wherein the one or more sustained-release pills are administered for approximately ten to approximately thirty days.
81 . The method of any one of claims 1 - 70 or 74 - 78 , wherein the one or more extended-release pills are administered for approximately thirty days or more.
82 . The method of any one of claims 1 - 70 or 74 - 78 , wherein the one or more extended-release pills are administered for approximately ten to approximately thirty days.
83 . The method of any one of claims 1 - 70 , 74 - 78 , 81 , or 82 , comprising a formulation of pirfenidone that provides release of pirfenidone over 12 hours.
84 . A pharmaceutical composition comprising pirfenidone and one or more excipients, for use in treating or preventing viremia caused by a virus, viremia-induced disease, COVID-19, a disease caused by a SARS-CoV-2 variant thereof, an infection with a virus, and/or ARDS caused by infection with an infectious agent in a subject in need thereof.
85 . The pharmaceutical composition of claim 84 , comprising pirfenidone and one or more excipients, for use in treating or preventing viremia caused by a virus, viremia-induced disease, an infection with a virus, and/or ARDS caused by infection with an infectious agent in a subject in need thereof.
86 . The pharmaceutical composition of claim 84 or 85 , wherein the pirfenidone is formulated in one or more sustained-release pills, wherein each of the one or more sustained-release pills comprises the pirfenidone and the one or more excipients.
87 . The pharmaceutical composition of claim 84 or 85 , wherein the pirfenidone is formulated in one or more extended-release pills, wherein each of the one or more extended-release pills comprises the pirfenidone and the one or more excipients.
88 . The pharmaceutical composition of claim 84 - 87 , wherein the viremia-induced disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
89 . The pharmaceutical composition of claim 84 - 88 , wherein the infection with the virus is infection with SARS-CoV-2.
90 . The pharmaceutical composition of any one of claims 84 - 89 , wherein the subject has COVID-19.
91 . Use of pirfenidone for treating or preventing viremia caused by a virus, viremia-induced disease, COVID-19, a disease caused by a SARS-CoV-2 variant thereof, an infection with a virus, and/or ARDS caused by infection with an infectious agent in a subject in need thereof.
92 . A kit comprising a pharmaceutical composition comprising pirfenidone and one or more excipients, for use in treating or preventing viremia caused by a virus, viremia-induced disease, COVID-19, a disease caused by a SARS-CoV-2 variant thereof, an infection with a virus, and/or ARDS caused by infection with an infectious agent; and
instructions for administering to a subject or contacting a biological sample with the pharmaceutical composition.