BANDYOPADHYAY SUSEN (US)
SINGH GURPARTAP (US)
RODRIGUEZ MEGHAN (US)
VALENTINO LEANN (US)
WO2019014247A1 | 2019-01-17 | |||
WO2018204198A1 | 2018-11-08 |
CN111494349A | 2020-08-07 | |||
CN111135166A | 2020-05-12 | |||
CN111603408A | 2020-09-01 | |||
CN112656759A | 2021-04-16 | |||
CN112675143A | 2021-04-20 | |||
US11020349B1 | 2021-06-01 |
SAHAKIJPIJARN SAWITTREE ET AL: "Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing", PHARMACEUTICS, vol. 12, no. 11, 1 November 2020 (2020-11-01), CH, pages 1002, XP055813173, ISSN: 1999-4923, DOI: 10.3390/pharmaceutics12111002
J. MED. CHEM., vol. 60, no. 5, 2017, pages 1648 - 166
Claims 1. A pharmaceutical composition comprising a compound of Formula (I) ula (I) or a pharmaceutically acceptable salt thereof; wherein X is selected from a hydroxyl, a metal salt hydroxylate, an O-linked phosphoester, an O-linked phosphoramidite, an O-linked ester, an O-linked carbamate, an S-linked phosphothioate, or an N-linked phosphoramidite, and at least one pharmaceutically acceptable excipient selected from a cysteine compound, an amino acid, an amino acid salt, an N-acetyl amino acid, an acid or a salt thereof, or any combination thereof. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is free of cyclodextrin. 3. The pharmaceutical composition according to any preceding claim, wherein the at least one pharmaceutically acceptable excipient comprises at least one cysteine compound. 4. The pharmaceutical composition according to any one of claim 3, wherein the at least one cysteine compound is cysteine hydrochloride and/or N-acetyl cysteine. 5. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition is a liquid formulation and wherein the pharmaceutical composition comprises one or more co-solvents. 6. The pharmaceutical composition according to claim 5, wherein the one or more co- solvents is selected from PEG, benzyl alcohol, ethanol or a combination thereof. 7. The pharmaceutical composition according to any one of claims 5-6 comprising 3-10 % w/w of compound of Formula (I) 0.5-30% w/w of a cysteine compound 50-86 % w/w of one or more co-solvent. 8. The pharmaceutical composition according to any one of the preceding claims, comprising one or more surfactants 9. The pharmaceutical composition according to claim 8, wherein the one or more surfactants comprises polysorbate. 10. The pharmaceutical composition according to claims 8 or 10, comprising 3-10 % w/w of compound of Formula (I) 1-15 % w/w cysteine hydrochloride monohydrate 3-15 % w/w N-acetyl cysteine 50-83 % w/w one or more co-solvent 2-8 % w/w surfactant. 11. The pharmaceutical composition according to any preceding claim, wherein the compound of Formula (I) is 12. A method of treating a viral infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-11. 13. The method according to claim 11, wherein the virus causing the viral infection is selected from a coronavirus, respiratory syncytial virus, ebola, hepatitis, junin, lassa fever, orthomyxovirus, Hepatitis Virus (HV) type, disease-causing picornavirus, Ebola, SARS, MERS, respiratory syncytial virus and other pneumovirus, influenza, polio measles and retrovirus including adult Human T-cell lymphotropic virus type 1 (HTLV- 1) and human immunodeficiency virus (HIV). 14. The method according to any one of claims 12-13, wherein the pharmaceutical composition is administered orally or parenterally. 15. A capsule comprising the pharmaceutical composition of any one of claims 1-11. 16. An oral solution comprising the pharmaceutical composition of any one of claims 1-11. 17. An injectable solution comprising the pharmaceutical composition of any one of claims 1-11. |
(A) In some embodiments, the O-linked phosphoramidite has the following structure, Compound (B), otherwise known as GS-6620. (B) In some embodiments, X is an O-linked phosphoester or an O-linked phosphoramidite with the following structure - Formula (II). I) wherein Y is O or NH, and wherein R 5 and R 6 may each be independently selected from C 1 -C 6 alkyl, C 2 -C 6 allyl, or C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl. In some embodiments, X is a hydroxyl group and the compound of Formula (I) has the structure as shown compound (C). Compound (C) can be made following the synthesis as described in J. Med. Chem.2017, 60, 5, 1648–166, the contents of which are incorporated by reference. This compound is otherwise known as GS-441524. p nd (C) In some embodiments of the compound of Formula (I), X is a salt hydroxylate. In some embodiments, the salt is selected from lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc a combination thereof. In some embodiments X is a metal salt hydroxylate, for example, wherein the metal salt is Li, Na, Ca, Mg, Zn, or K. In some embodiments, X is an O-linked ester. In some embodiments of X being an O-linked ester, X is an O-linked amino acid or an O-linked peptide. The O-linked peptide may comprise any number of amino acids, for example, from 2-10 amino acids. In some embodiments, the O-linked peptide is a dipeptide (i.e.2 amino acids), a tripeptide (i.e.3 amino acids), or a tetrapeptide (i.e.4 amino acids). In some embodiments, the O-linked peptide or O-linked amino acid is formed from any suitable natural or unnatural amino acid. In some embodiments, the amino acid is an L-amino acid, D-amino acid, or a combination thereof. In some embodiments, the amino acid is selected from alanine, valine, histidine, methionine, lysine, phenylalanine, threonine, tryptophan, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, proline, serine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan or a combination thereof. In some embodiments, the amino acid is selected from alanine, valine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan or a combination thereof. In some embodiments, the amino acids selected from alanine, valine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan or a combination thereof. In some embodiments X is an O-linked ester and the compound is of Formula (III) II) wherein R 7 may be selected from C 1 -C 6 alkyl, C 2 -C 6 allyl, or C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl. The compound of Formula (I) comprising X as an O-linked ester may be formed by selectivity esterifying the compound of Formula (I) wherein X is a hydroxyl group. In some examples, the compound of Formula (I) wherein X is a hydroxyl group may be reacted with the appropriate acid chloride (e.g. R 7 -C(=O)-Cl) or acid anhydride (R 7 -O-C(=O)-O-C(C=O)-R 7 ) or any other suitable esterification method known in the art. In some embodiments, X is an O-linked carbamate. In some embodiments X is an O-linked carbamate and the compound is of Formula (IV): V) wherein R 8 may be selected from H, C 1 -C 6 alkyl, C 2 -C 6 allyl, or C 2 -C 6 alkenyl, phenyl, biphenyl or heteroaryl. In some embodiments, X is an S-linked phosphothioate. In some embodiments X is an S-linked phosphothioate and the compound is of Formula (V): ) wherein R 9 and R 10 may each be selected from H, C 1 -C 6 alkyl, C 2 -C 6 allyl, or C 2 -C 6 alkenyl, phenyl, biphenyl or heteroaryl. In some embodiments, X is an S-linked phosphothioate, X may be: wherein R 11 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C 1 -C 6 alkyl, C 2 -C 6 -allyl, C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl, R12 is H, methyl, ethyl, isopropyl, isobutyl, secbutyl, phenyl, R13 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C 1 -C 6 alkyl, C 2 -C 6 allyl, or C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl. In some embodiments, X is an N-linked phosphoramidite. In some embodiments X is an N-linked phosphoramidite and the compound is of Formula (VI): wherein R 14 and R 15 may each be selected from H, C 1 -C 6 alkyl, C 2 -C 6 allyl, or C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl. In some embodiments, X is an N-linked phosphoramidite, X may be: wherein R16 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C1-C6 alkyl, C2- C 6 allyl, or C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl, R 17 is H, methyl, ethyl, isopropyl, isobutyl, secbutyl, phenyl, R 18 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C 1 -C 6 alkyl, C 2 -C 6 allyl, or C 2 - C 6 alkenyl, phenyl, biphenyl, heteroaryl. In some embodiments, for example, wherein X is a hydroxyl, a metal salt hydroxylate, an O-linked phosphoester, an O-linked phosphoramidite, an O-linked ester or an O-linked carbamate, the metabolized active product of the compound of Formula (I) is Compound (D) Compound (D) In other words, the compound of Formula (I) is capable of being metabolized to the compound (D) in the human or animal cell. Compound (D) is otherwise known as GS-443902. The compound of Compound (D) may be in ionized or non-ionized form. In some embodiments, the compound is capable of being metabolized to the monophosphate Compound (E) in the human or animal cell. Compound (E) is capable of being phosphorylated twice in the human or animal cell by one or more kinase enzymes. Compounds of Formula (I) wherein X is O-linked phosphoramidite and O-linked phosphoester can be first metabolised to Compound (E) by hydrolytic degradation, and thereby do not require monophosphorylation in the human or animal cell, a step that could be potentially rate-limiting. d (E) In some embodiments, for example, wherein X is: the compound of Formula (I) is metabolised to a compound of Formula (VII) VII) In some embodiments for example, wherein X is OH, a hydroxylate salt, an O-linked phosphoester or an O-linked phosphoramidite, an O-linked ester, an O-linked carbamate, the compound of Formula (I) is capable of being metabolised to the free hydroxyl (e.g. Compound (C)). In some embodiments, the compound of Formula (I) is metabolised to the free hydroxyl by esterase or amidase enzymes. In some embodiments, the compound of Formula (I) is metabolised to the free hydroxyl by hydrolytic degradation. The free hydroxyl is capable of being phosphorylated three times in the human or animal cell by one or more kinase enzymes, first to that of the monophosphate (i.e. Compound (E)), which is then further phosphorylated to the triphosphate (i.e. Compound (D)). In some embodiments, wherein X is an S-linked phosphothiaote, the metabolised active product of the compound of Formula (I) is Compound (F): p (F) In some embodiments, wherein X is an N-linked phosphoramidite, the metabolized active product of the compound of Formula (I) is Compound (G) (G) In some embodiments, the compound of Formula (I) has any suitable logP. In some embodiments, the compound of Formula (I) has a logP of less than 2.2. Remdesivir has a logP of 2.1. In alternative embodiments, the compound of Formula (I) has a log P of less than 2, or less than 1.8, or less than 1.6, or less than 1.4, or less than 1.2, or less than 1. In some embodiments, the compound of Formula (I) has a logP of greater than -1, or greater than -0.5, or greater than 0. In some embodiments, the compound of Formula (I) has a logP between -1 and 2.2, or between -1 and 2, or from 0 to 2.2, or between to 0 to 2. In some embodiments, the pharmaceutical composition comprises up to 15% w/w of Compound of Formula (I), or up to 14%, or up to 13%, or up to 12%, or up to 11%, or up to 10%, or up to 9 % w/w, or up to 8 % w/w, or up to 7 % w/w of compound of Formula (I). In some embodiments, the pharmaceutical composition comprises 0.05-20% w/w of compound of Formula (I), or 1-18% w/w, or 2-16% w/w, or 3-14% w/w, or 4-12 % w/w, or 5-10 % w/w, or 6-8 % w/w of compound of Formula (I). In example pharmaceutical compositions, the compound of Formula (I) is Remdesivir. Example Pharmaceutical Compositions In some embodiments, the pharmaceutical composition may comprise 0.05-20 % w/w compound of Formula (I), optionally 4-10% w/w, or optionally 5-7% w/w of compound of Formula (I), 0.5-50% w/w of at least one cysteine compound In some embodiments, the pharmaceutical composition may comprise 3-20 % w/w compound of Formula (I), optionally 4-10% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-35% w/w of at least one cysteine compound In some embodiments, the pharmaceutical composition may comprise 3-20 % w/w compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-30% w/w of at least one cysteine compound In some embodiments, the pharmaceutical composition may comprise 3-20 % w/w compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-50% w/w of at least one cysteine compound In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 0.5-35% at least one cysteine compound, 50-86 % w/w of one or more co-solvent In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-30% cysteine compound, 50-86 % w/w of one or more co-solvent In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-30% cysteine compound, 50-86 % w/w of one or more co-solvent 2-8% w/w surfactant In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-30% cysteine compound, 50-86 % w/w of one or more co-solvent 2-8% w/w polysorbate 80 In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 0.5-15 % w/w cysteine hydrochloride monohydrate, 0.5-15 % w/w N-acetyl cysteine In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-15 % w/w cysteine hydrochloride monohydrate, 1-15 % w/w N-acetyl cysteine 50-86 % w/w one or more co-solvent In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8 % w/w, optionally 5-7% w/w of compound of Formula (I) 1-15 % w/w cysteine hydrochloride monohydrate, 1-15 % w/w N-acetyl cysteine 50-83 % w/w one or more co-solvent 2-8% w/w surfactant In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8 % w/w, optionally 5-7% w/w of compound of Formula (I) 1-15 % w/w cysteine hydrochloride monohydrate, 1-15 % w/w N-acetyl cysteine 50-83 % w/w one or more co-solvent 2-8% w/w polysorbate 80 In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8 % w/w of compound of Formula (I), or 5- 7% w/w of compound of Formula (I). 1-15 % w/w cysteine hydrochloride monohydrate, 1-15 % w/w N-acetyl cysteine 2-8 % w/w polysorbate 80, 35-65 % w/w PEG 400 10-30 % w/w PEG 300 2-12% C2 to C7 alcohol In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8 % w/w of compound of Formula (I), or 5- 7% w/w of compound of Formula (I). 1-15 % w/w cysteine hydrochloride monohydrate, 2-8 w/w N-acetyl cysteine 2-8 % w/w polysorbate 80, 35-65 % w/w PEG 400 10-30 % w/w PEG 300 2-6 % w/w ethanol 2-6 % w/w benzyl alcohol In some embodiments of the above Example formulations, the pharmaceutical composition further comprises a poloxamer, e.g. poloxamer 188. The pharmaceutical composition may comprise 0.5-5% w/w poloxamer, e.g. poloxamer 188. The presence of a poloxamer may increase the stability of the Compound of Formula (I), e.g., Remdesivir. For example, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-30% cysteine compound, 50-86 % w/w of one or more co-solvent 2-8% w/w polysorbate 80 0.5-5% w/w poloxamer 188 For example, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8 % w/w, optionally 5-7% w/w of compound of Formula (I) 1-15 % w/w cysteine hydrochloride monohydrate, 1-15 % w/w N-acetyl cysteine 50-83 % w/w one or more co-solvent 2-8% w/w polysorbate 80 0.5-5% w/w poloxamer 188 In some embodiments of the above Example formulations, the pharmaceutical composition may further comprise a buffer such as tris (i.e. tromethamine). The pharmaceutical composition may comprise 0.25-5% w/w tris. For example, the pharmaceutical composition may comprise In some embodiments, the pharmaceutical composition may comprise 3-10 % w/w of compound of Formula (I), optionally 4-8% w/w, or optionally 5-7% w/w of compound of Formula (I), 1-30% cysteine compound, 50-86 % w/w of one or more co-solvent 2-8% w/w surfactant 0.25-5% w/w tris In some examples of the above Example formulations, the compound of Formula (I) is Remdesivir. In some embodiments the pharmaceutical composition may comprise one or more anti-oxidants. In some embodiments, the pharmaceutical composition is formulated such that the compound of Formula (I) has a solubility of greater than 0.01 mg/mL when placed in an aqueous solution at a pH 6.5, optionally greater than 0.05 mg/mL, optionally greater than 0.1 mg/mL when placed in an aqueous solution at a pH of 6.5 Formulation The pharmaceutical composition described herein may be formulated as any suitable formulation for therapeutic use. In some embodiments, the pharmaceutical composition is an oral formulation. The oral formulation is in the form of a solid oral dosage form, a liquid oral dosage form, a capsule, a tablet, a liquid- filled capsule, a caplet, a chewable gum, an oral film, an oral solution, a suspension, an emulsion, a lozenge, a wafer, a granulated powder formulation, a simple powder or mixture thereof, an elixir or a syrup that is capable of delivering the exact dose consistently to achieve adequate plasma concentrations of the compound of Formula(I) to bring about the intended therapeutic effect. In some embodiments, the tablet is an immediate release formulation. In some embodiments the tablet is a film-coated tablet. In some embodiments the tablet is an orally disintegrating tablet (ODT). In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation is used in an injectable solution. In some embodiments, the liquid formulation is used for oral administration, e.g., in a liquid-filled capsule or an oral solution. Capsule In another aspect, there is provided a capsule comprising the pharmaceutical composition of described herein. In some embodiments, the capsule is a liquid fill capsule. In some embodiments, the liquid fill capsule comprises a liquid formulation of the pharmaceutical composition as described herein. In an embodiment, the liquid fill capsule has a volume from about 0.4 mL to about 0.9 mL, optionally from about 0.6 mL to about 0.8 mL, optionally about 0.7 mL. In an embodiment the capsule comprises any suitable outer shell. In an embodiment the capsule is a hard gelatin capsule or a soft gelatin capsule. In an embodiment the outer shell comprises any suitable material, such as gelatin or hypromellose. In some embodiments, the concentration of the compound of Formula (I) in the liquid fill capsule is from 30 mg/mL to 100 mg/mL, or from 40 mg/mL to 80 mg/mL, or from 50 mg/mL to 75 mg/mL. Oral solution In another aspect, there is provide an oral solution comprising the pharmaceutical composition described herein. In an embodiment the oral solution comprises any liquid formulation of the pharmaceutical composition described herein further comprising sweeteners, common taste- masking agents, flavors and/or colors, the addition of which may make the composition more palatable. In an embodiment, the concentration of the active ingredient in the oral solution may be increased or decreased to allow measurement to be carried out in suitable manner depending on the conventional dosing devices used. Conventional dosing devices include a spoon, a dosing syringe, a dosing cup. The composition may be administered in the form of a medicine, a syrup, an elixir, syrup or a suspension. Injectable solution In another aspect, there is provided an injectable solution comprising the pharmaceutical composition described herein, which can be further diluted using standard intravenous infusion fluids to a target concentration of the active ingredient that is suitable for administration by intravenous infusion. In some embodiments, the final infusate following dilution with a standard infusion fluid medium is also an injectable solution, which comprises a pharmaceutically acceptable solvent or intravenous fluid medium. In some embodiments, the pharmaceutically acceptable solvent or intravenous fluid medium may be selected from sterile water-for-injection, one or more hypotonic solution(s), 0.9% sodium chloride solution (Normal Saline), 0.45% sodium chloride solution (half- normal saline), 0.225% sodium chloride solution (quarter-normal saline) and/or dextrose solution, for example, 5% dextrose (D5W). In some embodiments, the pharmaceutically acceptable solvent or intravenous fluid medium is an aqueous solution comprising 0.8 wt. % to about 1.0 wt. % sodium chloride, or about 0.9 wt. % sodium chloride. In some embodiments, the pharmaceutical composition comprises a solubilizing agent. In some embodiments, the solubilizing agent is a complexing agent. The solubilizing agent may be selected from a polymer, a chelating agent, a counter-ion (e.g. suitable salt-forming counter ion) or a combination thereof. The surfactant and co-solvent may also be considered to be a solubilizing agent. In some embodiments, the solubilizing agent encapsulates the compound of Formula (I) and can form, for example, a liposome or a micelle. In some embodiments, the solubilizing agent is a polymer. In some embodiments, the pharmaceutical composition comprises one, two, three, or four or more polymers. In some embodiments, the polymer may encapsulate the compound of Formula (I). In some embodiments, the polymer is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, shellac, cellulose acetate trimetallate, sodium alginate, zein, polyvinylpyrrolidone, poly(caprolactone) (PCL), poly(lactic-co- glycolic acid) (PLGA), poly(lactic acid) (PLA), (polyhydroxybutyrate) (PHB), poly(methysilsesquioxane) (PMSQ) or combinations thereof. In some embodiments, the polymer is a biodegradable (e.g. hydrolyzable) polymer, for example, PCL, PLGA, PLA or PHB. In some examples, the pharmaceutical composition comprises at least 0.1 wt. % polymer by weight, or at least 0.5 wt. %, or at least 1 wt. %, or at least 5 wt. %, or at least 10 wt. %, or at least 20 wt. % polymer by weight of the total pharmaceutical composition. In some embodiments, the solubilizing agent is a suitable counter ion (e.g. to form a salt). In some embodiments, the chelating agent may be selected from EDTA and salts thereof, citric acid, malic acid, malonic acid, oxalic acid, succinic acid, tartaric acid or a combination thereof. In some embodiments the pharmaceutical composition comprises a wetting agent. In some embodiments, the wetting agent is a selected from benzalkonium chloride, poloxamers (e.g. poloxamer 188, poloxamer 407), polysorbate, sodium lauryl sulfate, hypromellose or a combination thereof. In some embodiments the pharmaceutical composition comprises a solubilizing agent and a wetting agent. In some embodiment the pharmaceutical composition comprising a solubilizing agent in and amount of at least 0.1% (w/w) and a wetting agent in an amount of at least 0.1% (w/w). In some examples the pharmaceutical composition comprises PEG in the amount of 30% (w/w) and hypromellose in an amount of 0.5% (w/w). In some embodiments, the pharmaceutical composition is a compressed tablet. The compressed tablet comprises one or more compression aids and bulking agents, disintegrants, lubricants and wetting agents. The disintegrants may be selected from cross-linked carboxymethylcellulose (croscarmellose) sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium alginate, guar gum, cross-linked polyvinylpyrrolidone or crospovidone, cross-linked starch, sodium starch glycosylate, or any combination thereof. The disintegrants may increase the speed of release from the tablet and intestinal absorption of the compound of Formula (I). In some embodiments, the pharmaceutical composition is in the form of a tablet which comprises one or more disintegrants. In some examples, the pharmaceutical composition comprises at least 1 wt. % disintegrants by weight, or at least 5 wt. %, or at least 10 wt. %, or at least 20 wt. % disintegrants, by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein the tablet comprises a coating. In some embodiments, the coating comprises one or more of polyvinylalcohol, hydroxypropylmethocellulose, hydroxypropylcellulose, ethylcellulose, shellac, alginates, acrylate polymer, ferric oxide for color, or any combination thereof. In some embodiments the pharmaceutical composition is a direct compression tablet. In some embodiments, the pharmaceutical composition comprises pharmacologically acceptable excipients selected from a filler, a glidant, a lubricant, an anti-oxidant, a mucolytic agent, a buffer, a pH adjuster, a tonicity adjuster, or a combinations thereof. These excipients may be additional to or equivalent to the ones described above. In some embodiments, the filler may be selected from lactose, mannitol, sucrose, calcium sulphate, calcium phosphate, microcrystalline cellulose, xylitol, sorbitol, glucose, dextrose, mannose, maltitol or a combination thereof. In some embodiments, the lubricant and glidant may independently be selected from a fatty acid, fatty acid salts, fatty acid monoglycerides, fatty acid triglycerides, fatty acid esters, talc, silica (for example, colloidal silica), or a combination thereof. The fatty acids may be a saturated or unsaturated fatty acid. The fatty acid may be a C 10 -C 22 fatty acid. In some examples, the lubricant is selected from stearic acid, magnesium stearate, sodium behenate and/or sodium stearyl fumarate. In some embodiments, the anti-oxidant is selected from ascorbic acid, citric acid, sodium citrate, vitamin A, vitamin E, cysteine hydrochloride, methionine or a combination thereof. In some embodiments, the buffer may be selected from hydrochloric acid, sodium hydroxide tris, acetate, citrate, tartaric acid or salts thereof, lactic acid and salts thereof, phosphates, benzoates, bicarbonate, carbonates, sulphates, sodium chloride, potassium chloride, calcium chloride, tromethamine or a combination thereof. In some embodiments, the buffer may be tris. The buffer may be included to improve the stability of the Compound of Formula (I), e.g., Remdesivir. In some embodiments, the pharmaceutical composition may comprise up to about 5 % buffer by weight of the pharmaceutical composition, or up to about 2% buffer by weight of the pharmaceutical composition, or from about 0.5 to about 1 % buffer by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition may comprise up to about 2 % tris by weight of the pharmaceutical composition, or from about 0.5 to about 1 % tris by weight of the pharmaceutical composition. In some embodiments, the pH adjuster may be selected from hydroxides (e.g. sodium, magnesium, calcium, potassium), metal oxides (e.g., magnesium, calcium) acetic acid or salts thereof, citric acid or salts thereof, tartaric acid or salts thereof, lactic acid and salts thereof, gluconic acid and salts thereof, phosphates, pyrophosphates, benzoates, bicarbonate, carbonates, sulphates, sodium chloride, potassium chloride or a combination thereof, meglumine, adipic acid or salts thereof, tartaric acid or salts thereof, fumaric acid or salts thereof, gluconic acid or salts thereof, itaconic acids or salts thereof, ammonium aluminium sulfate, ammonium bicarbonate, ammonium hydroxide. In some embodiments, the pH of the pharmaceutical composition in solution or as a suspension is from 1 to 11. In some embodiments, the pH of the pharmaceutical composition is slightly basic, for example, from 7.5 to 8. In some embodiments the pH of the pharmaceutical composition is slightly acidic, for example, less than 7, from 1 to <7, of from 1.5 to 6.75, or from 2 to 6.5, or from 4 to 6.75, or from 4 to 6.5, or from 4 to <7, or from 5 to 6.5, or from 5 to <7, or from 6 to <7, or from 6.5 to <7, or from 3 to 6, 4 to 6, 5 to 6, or 3 to 5, or 4 to 5, or 3 to 4. The pH of the pharmaceutical composition can alter the solubility and promote dissolution of the compound of Formula (I) and/or metabolites. In some embodiments, an acidic pH promotes the dissolution of a compound of Formula (I). In some embodiments, the mucolytic agent may be N-acetyl cysteine or cysteine hydrochloride. In some embodiments, the tonicity adjuster may be selected from dextrose, glycerin, mannitol, potassium chloride, sodium chloride or a combination thereof. The pharmaceutical composition described herein may comprise from 10 mg to 1000 mg of Formula (I), or from about 100 mg to 1000 mg, or from about 20 mg to about 300 mg, or about 100 mg to 200 mg. The pharmaceutical composition described herein may comprise greater than 50mg, or greater than 100 mg, or greater than 150 mg, or greater than 200 mg, or greater than 250 mg, or greater than 300 mg, or greater than 350 mg, or greater than 400 mg, or greater than 500 mg, or greater than 550 mg, or greater than 600 mg of Formula (I). In some cases, the pharmaceutical composition may comprise less than 1000 mg, or less than 500 mg, or less than 200 mg. In some cases, the oral dosage of Formula (I) may be larger than that used for intravenous injection because the mode of administration is different. The oral dosage may comprise one or more tablets, for example, two tablets, three tablets, or four tablets. The oral dosage may comprise one or more capsules, for example, two capsules, three capsules, or four capsules. The pharmaceutical compositions described herein may have good shelf-life and/or stability. The stability of the pharmaceutical composition of the present invention may be monitored using a number of methods. The stability may be determined by establishing the initial amount of compound of Formula (I), and then measuring the amount of compound of Formula (I) remaining after a certain time thereafter and comparing the two values. The initial amount of the compound of Formula (I) is the amount present immediately after mixing all the components of the composition. The amount of compound of Formula (I) present may be measured using a range of methods known in the art, such as HPLC, mass spectrometry, spectrophotometry, gel electrophoresis, Western Blotting, light scattering, microbiological or other biological activity measuring assays. A typical method of tracking stability would constitute comparing the purity of the compound of Formula (I) in a given product pharmaceutical composition against that of a freshly prepared standard to calculate the amount of non-degraded compound of Formula (I) in the product for any given sample. Samples that are stored and analyzed over various periods of time would then provide a quantitative profile of the purity of the compound of Formula (I) over time. Optionally, the degradation rate of the compound of Formula (I) under stressed conditions of storage, such as at an elevated temperature, can then be determined from the decreasing purity versus time profile by fitting suitable regression lines or curves. Such degradation rates generated from stressed stability studies are particularly useful in comparing between different product pharmaceutical compositions over a short period of time. In certain embodiments, at least 90% by weight of the compound of Formula (I) is present in the pharmaceutical composition after being stored for 30 days at from about 20 °C to about 25 °C, based on the initial amount of the compound of Formula (I) in the pharmaceutical composition. For example, at least 92%, or at least 94%, or at least 96%, or at least 98% of the compound of Formula (I) is present in the composition after being stored for 30 days at from about 20 to about 25 °C, based on the initial amount of the compound of Formula (I) in the pharmaceutical composition. In some examples, the composition is stored at about 25 °C, or at about 24 °C, or at about 23 °C, or at about 22 °C, or at about 21 °C. The purity of the composition according to the present invention may be monitored using one or more analytical methods from those listed before that are most suited for compound of Formula (I) in question. The loss in purity may be determined by subtracting the purity of the compound of Formula (I) in the product at any given time from that immediately after manufacturing of the product (time t0). The difference in purities would constitute the loss of purity over the time period of testing. Alternatively, the purity of the compound of Formula (I) could be measured at various time points from samples that are manufactured and stored in suitable sealed containers, which represent the unit dosage form. The purities are then plotted against time and fitted to a regression line, if linear, to determine an overall pseudo first- order degradation rate from the slope of such regression line. The pharmaceutical composition described herein has good bioavailability. In some embodiments, the pharmaceutical composition described herein has good bioavailability when administered orally. In some embodiments, the bioavailability is at least 2.5%, or at least 3%, or at least 3.5%, or at least 4%, or at least 4.5%, or at least 5%, or at least 5.5%, or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8 %, or at least 8.5%, or at least 9 %, or at least 9.5%, or at least 10%, or at least 12.5%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50 % of the active ingredient or a metabolite formed in the body as a consequence of action of enzymes on the active ingredient as compared to when administered intravenously. In this case, the oral bioavailability is defined as AUC [(oral)/AUC(IV)] * 100. Method of treating a viral infection In a second aspect, there is provided a method of treating a viral infection, the method comprising administering to a subject in need thereof a therapeutically effective amount any pharmaceutical composition described herein. In some embodiments, the viral infection is an RNA viral infection. In some embodiments, virus causing the viral infection is a human-disease causing virus. In some embodiments, the virus may be coronavirus, respiratory syncytial virus, ebola, hepatitis, junin, lassa fever, orthomyxovirus, Hepatitis Virus (HV) type, disease-causing picornavirus, Ebola, SARS, MERS, respiratory syncytial virus and other pneumovirus, influenza, polio measles and retrovirus including adult Human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV). In some embodiments, the RNA virus may be a coronavirus. In some embodiments, the coronavirus is a coronavirus causing disease in humans. In some embodiments, the virus may be a coronavirus that causes disease in non-human animal species, such as, the feline infectious peritonitis virus, the porcine deltacorona virus. In some embodiments, the viral infection is a coronavirus infection. The coronavirus infection may be caused by any type or strain of coronavirus. In some embodiments, the coronavirus infection may be an alphacoronavirus infection or a betacoronavirus infection, preferably a betacoronavirus. The betacoronavirus may have an A lineage, a B lineage, a C lineage or a D lineage, for example, a B lineage. In preferred embodiments, the coronavirus infection may be COVID-19, otherwise known as SARS-CoV-2 or 2019-nCoV. In some embodiments, the pharmaceutical composition described herein may be administered in circumstances where there is an anticipated risk of infection for prophylactic use to prevent such infection or, at the very least, to prevent severe manifestations of the disease. In some embodiments, the pharmaceutical composition may be administered using any suitable administration method. In an embodiment, the pharmaceutical composition is administered orally, parenterally, by inhalation or by nebulisation, or by intratracheal instillation. In an embodiment, the pharmaceutical composition is administered such that there is targeted delivery of the Compound of Formula (I) to the site of viral infection, e.g., in the case of SARS-CoV-2 to the lung, for example, to lung alveolar cells. Targeted drug delivery refers to any method of drug delivery that increases the concentration of the medication in some parts of the body relative to the others. In some embodiments, the pharmaceutical composition may be administered by injection. In some embodiments, the injection may be an intravenous injection or a subcutaneous injection. In some instances, subcutaneous injection can be advantageous because it is often non-intrusive, safe, well-tolerated, and/or requires reduced resource use due to reduced need for specialized skills or monitoring during administration. In some embodiments, the pharmaceutical composition may be administered orally. In some embodiments, the pharmaceutical composition described herein may be administered less than 4 days after exposure to a COVID-19 case (e.g. another positive case), or less than 3 days after exposure, or less than 2 days after exposure, or within a day of exposure, or within an hour of exposure to a COVID-19 case. In some embodiments, the pharmaceutical composition described herein may be administered to prevent a possible viral exposure to an otherwise healthy individual without any notable signs or symptoms of the disease primarily for the purpose of prophylactic prevention of infection. In some embodiments, the pharmaceutical composition described herein may alleviate one or more of the following symptoms caused by COVID-19: cough, sore throat, a high temperature or fever, loss of smell or taste, difficulty in breathing, tiredness, muscle pain, chest pain, runny nose, headache, chills, or any combination thereof. In some embodiments, the viral infection is a hepatitis infection. The hepatitis infection may be hepatitis A, B, C, D or E. The hepatitis infection may be acute hepatitis, fulminant hepatitis or chronic hepatitis. In some embodiments, the pharmaceutical composition described herein is administered from every 4 hours up to every 4 weeks. In an embodiment, the pharmaceutical composition described herein is administered every 4 hours, or up to every 8 hours, or up to every 12 hours, or up to every 16 hours, or up to every 24 hours, or up to every 48 hours, or up to every 36 hours, or up to every 72 hours, or up to every 144 hours, or up to every week, or up to every 2 weeks, or up to every 4 weeks. The compound of Formula (I) may be administered more frequently if the symptoms are more severe. An effective amount of the pharmaceutical composition described herein may be administered in either single or multiple doses. The multiple doses may be taken at the same time, or at different timepoints in the day (e.g. once, twice, three times, four times, five times or even six times a day). The amount of the compound to be administered (i.e. the dosage) is dependent on the specific viral infection being treated, the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, the bioavailability of the specific compound, and its effective inhibitory concentration (IC50) against the specific virus infection being treated. In an embodiment, the dosage of the compound of Formula (I) is from about 2 to 20 mg/kg, for example, 3 to 18 mg/kg, 5 to 15 mg/kg, 7 to 14 mg/kg or 10 to 12 mg/kg. In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments the amount of liquid formulation administered is about 1 mL to about 40mL of liquid formulation, for example about 3 mL to about 35 mL, or about 5 mL to about 30 mL, or about 10 mL to about 30 mL, or about 10 mL to about 25 mL, or about 15 mL to about 25 mL. In some embodiments the amount of compound of Formula (I) administered to the subject is from 10 to 1000 mg, or from 20 to 300 mg, or from 100 to 200 mg of compound of Formula (I). In some embodiments, the liquid formulation is administered as a liquid-filled capsule as described herein. In some embodiments, more than one liquid filled capsule is administered to the subject, or more than two, or more than three, or more than four liquid filled capsules are administered to the subject. In some embodiments of the method, the compound of Formula (I) is metabolized to the active metabolite (triphosphate - Compound (D)) such that the active metabolite is present at a concentration of at least 0.02 µM, or at least 0.04 µM, or at least 0.06 µM, or at least 0.08 µM, or at least 0.1 µM, or at least 0.15 µM in the peripheral blood cells and/or target tissues. In some embodiments of the method, the compound of Formula (I) is metabolized to the active metabolite (triphosphate - Compound (D)) such that the peak concentration of the active metabolite is at least 0.5 µM, or at least 0.7 µM, or at least 1 µM, or at least 10 µM in the peripheral blood cells and/or target tissues. p (D) In some embodiments of the method, the bioavailability of the compound of Formula (I) after administration as measured in terms of the compound of Formula (I) or any of its direct metabolites in the blood, such as, Compound (C) [GS-441524] is at least 3%, or at least 5% or at least 7%, or at least 10%, or at least 50%, or at least 80%, or at least 90% as measured by the area under the plasma concentration versus time curve (AUC). In some embodiments of the method, the bioavailability of Formula (I) inside peripheral blood cells, when measured in terms of Compound (D), after administration, is at least 3%, or at least 5% or at least 7%, or at least 10%, or at least 50%, or at least 80% as measured by the area under the concentration in peripheral blood cells versus time curve (AUC). In some embodiments of the method, the bioavailability of the compound of Formula (I) after oral administration is at least 2.5%,or at least 3%, or at least 3.5%, or at least 4%, or at least 4.5%, or at least 5%, or at least 5.5%, or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8 %, or at least 8.5%, or at least 9 %, or at least 9.5%, or at least 10%, or at least 12.5%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50 as compared to intravenous administration. In some embodiments of the method, the oral bioavailability of Compound (C) (i.e. the nucleoside analog GS-441524) as measured with respect to the intravenous dose of the compound of Formula (I), and as measured from the concentration of Compound (C) in the blood after oral administration of compound of Formula (I) is at least 2.5%,or at least 3%, or at least 3.5%, or at least 4%, or at least 4.5%, or at least 5%, or at least 5.5%, or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8 %, or at least 8.5%, or at least 9 %, or at least 9.5%, or at least 10%, or at least 12.5%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50% or at least 60%, or at least 70%, or at least 80% as compared to intravenous administration of the compound of Formula (I). In some embodiments of the method, the oral bioavailability of Compound (D) (i.e. the active triphosphate) as measured with respect to the intravenous dose of the compound of Formula (I), and as measured from the concentration of Compound (D) in peripheral blood cells after oral administration of compound of Formula (I) is at least 2.5%,or at least 3%, or at least 3.5%, or at least 4%, or at least 4.5%, or at least 5%, or at least 5.5%, or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8 %, or at least 8.5%, or at least 9 %, or at least 9.5%, or at least 10%, or at least 12.5%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50 as compared to intravenous administration of the compound of Formula (I).
The present disclosure may be described by one or more of the following paragraphs: A. An oral formulation comprising a compound of Formula (I) B. ) wherein X is selected from a hydroxyl, a metal salt hydroxylate, an O-linked phosphoester, an O-linked phosphoramidite, an O-linked ester, an O-linked carbamate, an S-linked phosphothioate, or an N-linked phosphoramidite. B. The oral formulation of paragraph A, wherein the compound of Formula (I) is a prodrug. C. The oral formulation according to paragraph A, wherein X is an O-linked phosphoramidite or an O-linked phosphoester. D. The oral formulation according to any of the preceding paragraphs, wherein X is an O- linked phosphoramidite with formula wherein R 2 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C 1 -C 6 alkyl, C 2 -C 6 -allyl, C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl, R 3 is H or C 1 -C 6 alkyl; and R 4 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C 1 -C 6 alkyl, C 2 -C 6 -allyl, C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl, E. The oral formulation according to paragraph D, wherein R 3 is methyl. F. The oral formulation according to any one of paragraphs A to C, wherein X is an O-linked phosphoramidite with formula wherein R 2 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C 1 -C 6 alkyl, C 2 -C 6 -allyl, C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl, R 3 is H, methyl, ethyl, isopropyl, isobutyl, secbutyl, phenyl, R 4 is H, lithium, sodium, potassium, aluminium, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine, procaine, trimethylamine, zinc, C 1 -C 6 alkyl, C 2 -C 6 -allyl, C 2 -C 6 alkenyl, phenyl, biphenyl, heteroaryl. G. The oral formulation according to any of the preceding paragraphs, wherein the compound of Formula (I) is H. The oral formulation according to paragraph A, wherein X is a hydroxyl, a metal salt hydroxylate, an O-linked ester or an O-linked carbamate. I. The oral formulation according to paragraph A or paragraph H, wherein the O-linked ester is an O-linked amino acid or an O-linked peptide. J. The oral formulation according to paragraph I, wherein the O-linked amino acid or O- linked peptide is formed from amino acids selected from alanine, valine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan or a combination thereof. K. The oral formulation according to any preceding paragraph, wherein the compound of Formula (I) has a logP less than 2. L. The oral formulation according to any preceding paragraph, wherein the compound of Formula (I) has a logS greater than -2. M. The oral formulation according to any one of the preceding paragraphs, wherein the metabolised active product of compound of Formula (I) is Compound (D) nd (D) N. The oral formulation according to any one of the preceding paragraphs, wherein the oral formulation is in the form of a solid oral dosage form, a liquid oral dosage form, a capsule, a tablet, a liquid-filled capsule, a caplet, a chewable gum, an oral film, an oral solution, a suspension, an emulsion, a lozenge, a wafer, a granulated powder formulation, a simple powder or mixture thereof, an elixir or a syrup. O. The oral formulation according to any one of the preceding paragraphs that is free from cyclodextrins. P. The oral formulation according to any one of the preceding paragraphs, further comprising a solubilizing agent. Q. The oral formulation according to paragraph P, wherein the solubilizing agent encapsulates the compound of Formula (I). R. The oral formulation according to any one of paragraphs P or Q wherein the solubilizing agent is selected from a liposome, a micelle, a polymer, a surfactant, a co-solvent, a chelating agent, a counter-ion or a combination thereof. S. The oral formulation according to paragraph R, wherein the solubilizing agent is a polymer, and wherein the polymer is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, shellac, cellulose acetate trimetallate, sodium alginate, zein, polyvinylpyrrolidone, poly(caprolactone), poly(lactic-co-glycolic acid), poly(lactic acid), poly(hydroxybutyrate), poly(methylsilsesquioxane) or a combination thereof. T. The oral formulation according to paragraph S, wherein the polymer is a biodegradable polymer, optionally selected from poly(caprolactone), poly(lactic-co-glycolic acid), poly(lactic acid) and/or poly(hydroxybutyrate). U. The oral formulation according to paragraph R, wherein the solublising agent is a co- solvent, and wherein the co-solvent is selected from PEG, glycerol, glycofural, DMSO, ethanol, propylene glycol, methyl lactate, ethyl lactate, propyl lactate, spironolactone, N- methylpyrrolidone, benzyl alcohol, cetostearyl alcohol, benzylbenzoate, corn syrup, acacia syrup, glucose syrup, acetyltributyl citrate, lactic acid, acetic acid, ethylacetate, benzoic acid, polyoxyl 35 castor oil, polysorbate 20, 40, and 80; water; mineral oils, edible hydrogenated oils; edible non-hydrogenated edible oils or a combination thereof. V. The oral formulation according to paragraph R, wherein the solubilising agent is a counter-ion, wherein the counter-ion is a metal ion, and wherein the metal-ion is selected from Ag + , Fe 2+ , Fe 3+ , Co 2+ , Co 3+ , Cu 2+, Zn 2+ , or a combination thereof. W. The oral formulation according to paragraph R, wherein the solubilizing agent is a chelating agent, and wherein the chelating agent is selected from EDTA and salts thereof, citric acid, malic acid, malonic acid, oxalic acid, succinic acid, tartaric acid or a combination thereof. X. The oral formulation according any of the preceding paragraphs, further comprising one or more wetting agent selected from benzalkonium chloride, poloxamers (e.g. poloxamer 188, poloxamer 407), polysorbate, sodium lauryl sufate, hypromellose or a combination thereof. Y. The oral formulation according any of the preceding paragraphs, further comprising one or more disintegrants selected from cross-linked carboxymethylcellulose (croscarmellose) sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium alginate, guar gum, cross-linked polyvinylpyrrolidone or crospovidone, cross-linked starch, sodium starch glycosylate, or any combination thereof. Z. The oral formulation any of the preceding paragraphs, wherein the oral formulation is a tablet, and wherein the tablet comprises a coating comprising one or more of polyvinylalcohol, hydroxypropylmethocellulose, hydroxypropylcellulose, ethylcellulose, shellac, alginates, acrylate polymer, ferric oxide or a combination thereof. AA. The oral formulation according to any one of the preceding paragraphs further comprising one or more pharmacologically acceptable excipients selected from a filler, a glidant, a lubricant, an anti-oxidant, a mucolytic agent, a buffer, a pH adjuster, a tonicity adjuster, or a combination thereof. BB. The oral formulating according to paragraph AA, wherein the filler is selected from lactose, mannitol, sucrose, calcium sulphate, calcium phosphate, microcrystalline cellulose, xylitol, sorbitol, glucose, dextrose, mannose, maltitol or a combination thereof. CC. The oral formulation according to paragraph AA, wherein the lubricant is selected from a vegetable oil, an animal oil, a fatty acid, fatty acid salts, fatty acid monoglycerides, fatty acid triglycerides, talc, silica, or a combination thereof. DD. The oral formulation according to paragraph AA, wherein the anti-oxidant is selected from ascorbic acid, citric acid, sodium citrate, vitamin A, vitamin E, cysteine hydrochloride, methionine or a combination thereof. EE. The oral formulation according to any one the preceding paragraphs comprising 10 mg to 1000 mg of the compound of Formula (I), or from about 100 mg to 1000 mg of the compound of Formula (I). FF. A method of treating a RNA viral infection, the method comprising orally administering to a subject in need thereof a therapeutically effective amount the oral formulation of any one of paragraphs A-Z or AA-EE. GG. The method according to paragraph FF, wherein the viral infection is a coronavirus infection. HH. The method according to paragraph FF, wherein the coronavirus infection is COVID- 19. II. The method according to paragraph FF, wherein the viral infection is a hepatitis infection. JJ. The method according to any one of paragraphs FF to II, wherein the oral formulation is administered from every 4 hours up to every 4 weeks. KK. The method according to any one of paragraphs FF to JJ, wherein the compound of Formula (I) is metabolized to the active metabolite of Compound (D) such that the active metabolite is present at a concentration of at least 0.1 µM in the peripheral blood cells and/or target tissues. (D) LL. The method according to any one of paragraphs FF to KK, wherein the bioavailability of the compound of Formula (I) is at least 5% after oral administration.
The present disclosure may also be described by one or more of the following paragraphs: a. A pharmaceutical composition comprising a compound of Formula (I) b. wherein X is selected from a hydroxyl, a metal salt hydroxylate, an O-linked phosphoester, an O-linked phosphoramidite, an O-linked ester, an O-linked carbamate, an S-linked phosphothioate, or an N-linked phosphoramidite, and at least one pharmaceutically acceptable excipient selected from a cysteine compound, an amino acid, an amino acid salt, an N-acetyl amino acid, an organic acid or a salt thereof, or any combination thereof. b. The pharmaceutical composition according to paragraph a, wherein the pharmaceutical composition is free of cyclodextrin. c. The pharmaceutical composition according to paragraph a or paragraph b, wherein the composition is a solution, a suspension or a mixture thereof. d. The pharmaceutical composition according to any preceding paragraph, wherein the pharmaceutical composition is an oral formulation or a parenteral formulation. e. The pharmaceutical composition according to any preceding paragraph, wherein the at least one pharmaceutically acceptable excipient comprises an acid or a salt thereof, and optionally wherein the acid is an organic acid selected from lactic acid, acetic acid, adipic acid, citric acid, formic acid, succinic acid oxalic acid, ascorbic acid, uric acid, malic acid, tartaric acid or any combination thereof. f. The pharmaceutical composition according to any preceding paragraph, wherein the at least one pharmaceutically acceptable excipient comprises at least one cysteine compound. g. The pharmaceutical composition according to paragraph f, wherein the % w/w ratio of the at least one cysteine compound to the compound of Formula (I) is at least 1:1, optionally greater than 1.5:1. h. The pharmaceutical composition according to any one of paragraphs f-g, comprising a. 0.05-20 % w/w compound of Formula (I) b. 0.5-50 % w/w of at least one cysteine compound. i. The pharmaceutical composition according to any one of paragraphs f-h, comprising a. 4-8 % w/w compound of Formula (I), optionally 5-7% w/w compound of Formula (I) and b. 1-30 % w/w of at least one cysteine compound. j. The pharmaceutical composition according to any one of paragraphs f-i, wherein the at least one cysteine compound comprises cysteine, glutathione, cysteine hydrochloride and/or N-acetyl cysteine or a combination thereof. k. The pharmaceutical composition according to any one of paragraphs f-j, wherein the at least one cysteine compound is cysteine hydrochloride and/or N-acetyl cysteine. l. The pharmaceutical composition according to any one of paragraphs f-k, wherein the at least one cysteine compound is cysteine hydrochloride and N-acetyl cysteine. m. The pharmaceutical composition according to any one of paragraphs f-l comprising a. 3-10 % w/w of compound of Formula (I) b. 0.5-15 % w/w cysteine hydrochloride monohydrate c. 0.5-15 % w/w N-acetyl cysteine. n. The pharmaceutical composition according to any preceding paragraph, wherein the pharmaceutical composition is a liquid formulation. o. The pharmaceutical composition according to paragraph n, wherein the pharmaceutical composition comprises one or more co-solvents. p. The pharmaceutical composition according to any one of paragraphs n-o, wherein the liquid formulation has a pH of less than 8.5, optionally wherein the pH is in the range of 1-<8. q. The pharmaceutical composition according to any one of paragraphs n-p comprising a. 3-10 % w/w of compound of Formula (I) b. 0.5-30% w/w a cysteine compound c. 50-86 % w/w of one or more co-solvent. r. The pharmaceutical composition according to paragraphs n-q comprising a. 3-10 % w/w of compound of Formula (I) b. 1-15 % w/w cysteine hydrochloride monohydrate, c. 3-15 % w/w N-acetyl cysteine d. 50-86 % w/w one or more co-solvent. s. The pharmaceutical composition according to paragraph n-r, wherein the one or more co-solvents is selected from PEG, benzyl alcohol, ethanol or a combination thereof. t. The pharmaceutical composition according to paragraph n-s, wherein the one or more co-solvents comprises low molecular weight polyethylene glycols (PEG), propylene glycol, benzyl alcohol, ethanol or a combination thereof. u. The pharmaceutical composition according to paragraph t, wherein the PEG has a molecular weight from 200 to 1000. v. The pharmaceutical composition according to any one of the preceding paragraphs, comprising one or more surfactants. w. The pharmaceutical composition according to paragraph v, wherein the one or more surfactants is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl 35 castor oil, cremophor, polyoxyethylene (20) sorbitan monooleate, polyethylene glycol sorbitan monooleate, polyoxyethylenesorbitan monooleate, or a block copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), such as, poloxamer, or a combination thereof. x. The pharmaceutical composition according to any one of paragraphs v-w, wherein the HLB value of the one or more surfactant is from 10-20, optionally from 12 to 18, or optionally from 14 to 16. y. The pharmaceutical composition according to any one of paragraphs v-x, wherein the one or more surfactants is polysorbate. z. The pharmaceutical composition according to any one of paragraphs v-y, comprising a. 3-10 % w/w of compound of Formula (I) b. 1-15 % w/w cysteine hydrochloride monohydrate c. 3-15 % w/w N-acetyl cysteine d. 50-83 % w/w one or more co-solvent e. 2-8 % w/w surfactant. aa. The pharmaceutical composition according to any one of paragraphs x-z comprising a. 3-10 % w/w of compound of Formula (I) b. 1-15 % w/w cysteine hydrochloride monohydrate c. 3-15 % w/w N-acetyl cysteine d. 4-8 % w/w polysorbate 80 e. 35-60 % w/w PEG 400 f. 10-30 % w/w PEG 300 g. % w/w ethanol h. % w/w benzyl alcohol. bb. The pharmaceutical composition according to any one of the preceding paragraphs, comprising one or more anti-oxidants. cc. The pharmaceutical composition according to any one of the preceding paragraphs, wherein the metabolised active product of compound of Formula (I) is Compound (D) dd. Compound (D) ee. The pharmaceutical composition according to any preceding paragraph, wherein the compound of Formula (I) is ff. gg. The pharmaceutical composition according to any preceding paragraph, wherein the pharmaceutical composition is formulated such that the compound of Formula (I) has a solubility of greater than 0.05 mg/mL when placed in an aqueous solution at pH 6.5. hh. A method of treating a viral infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of paragraphs a-gg. ii. The method according to paragraph hh, wherein the virus causing the viral infection is selected from a coronavirus, respiratory syncytial virus, ebola, hepatitis, junin, lassa fever, orthomyxovirus, Hepatitis Virus (HV) type, disease-causing picornavirus, Ebola, SARS, MERS, respiratory syncytial virus and other pneumovirus, influenza, polio measles and retrovirus including adult Human T-cell lymphotropic virus type 1 (HTLV- 1) and human immunodeficiency virus (HIV). jj. The method according to paragraph hh, wherein the viral infection is a coronavirus infection. kk. The method according to paragraph jj, wherein the coronavirus infection is SARS- CoV-2. ll. The method according to any one of paragraphs hh-jj, wherein the amount of the compound of Formula (I) administered is from about 20 mg to about 300 mg, or from about 50 mg to 250 mg. mm. The method according to any one of paragraphs hh-ll, wherein the pharmaceutical composition is a liquid formulation and optionally wherein the amount of liquid formulation dosed is from about 1 mL to about 40 mL of the undiluted liquid formulation. nn. The method according to any one of paragraphs hh-mm, wherein the pharmaceutical composition is administered orally. oo. The method according to any one of paragraphs hh-nn, wherein the pharmaceutical composition is administered by injection. pp. The method for use according to paragraph oo, wherein the injection is an intravenous injection or a subcutaneous injection. qq. The method for use according to paragraph pp, wherein the injection is an intravenous injection or a subcutaneous injection that is administered following dilution with an intravenous infusion fluid to a final infusate volume of 100 to 250 mL. rr. A capsule comprising the pharmaceutical composition of any one of paragraphs a-gg. ss. A capsule according to paragraph rr, wherein the capsule is a liquid fill capsule. tt. A capsule according to paragraph ss, wherein the liquid fill capsule has a volume from about 0.4 mL to about 0.9 mL, optionally from about 0.6 mL to about 0.8 mL, optionally about 0.7 mL. uu. An oral solution comprising the pharmaceutical composition of any one of paragraphs a-gg. vv. An injectable solution comprising the pharmaceutical composition of any one of paragraphs a-gg. Examples Effect of pharmaceutical excipients on solubility Various compounds were tested in combination with Remdesivir to see if the compounds had a solubilizing effect. The present inventors found that cysteine-compounds in particular (e.g. cysteine hydrochloride, N-acetyl cysteine, L-cysteine and glutathione) all demonstrated a solubilizing effect on Remdesivir, with solubility being greater > 0.01 mg/mL for all cysteine- related compounds at concentrations that are suitable for administration. Furthermore, certain cysteine compounds, namely cysteine hydrochloride and N-acetyl cysteine were shown to improve Remdesivir solubility to an amount > 0.2 mg/mL at concentrations of excipients that are suitable for administration by oral and parenteral routes. Without wishing to be bound by theory, in addition to any innate effect on solubility, the improvements of solubility of Remdesivir in solutions of cysteine hydrochloride and N-acetyl cysteine may be further attributed to a slight acidifying effect of these compounds. N-acetyl amino acids, e.g. both N-acetyl cysteine and N-acetyl D-alanine, also showed a significant solubilizing effect. Table 1 – Pharmaceutical excipients and their effects on Remdesivir solubility at concentrations of these excipients in water that may be justified by the maximum daily intakes for each (MDI)† † MDI or maximum daily intake is based on FDAs IIG database for approved oral dosage forms when diluted in 250 mL of water. This is to reflect final concentrations of these excipients that could be achieved in the intestine, if the maximum approved intake is administered along with the daily dose of the drug. Due to the good results observed with cysteine HCl and N-acetyl cysteine, these were compared against sulfobutylether β cyclodextrin (SBEβCD), which is the known excipient used in Remdesivir formulations. The concentration of SBEβCD used was 11.8 mg/mL, which corresponds to approximately 3 g of SBEβCD dissolved in 250 mL of intestinal fluid which is approximately the same amount of SBEβCD (3 g) used for every 100 mg Remdesivir in the freeze-dried injectable formulation used commercially. As can be seen from Table 2, both cysteine hydrochloride and N-acetyl cysteine solubilized Remdesivir more effectively than SBEβCD on a weight basis. This indicates that the pharmaceutical compositions described herein may offer an alternative strategy of solubilizing and administering Remdesivir to improve its oral bioavailability, or for the intravenous administration of Remdesivir to patients with impaired kidneys, who may not be able to receive the current product containing high amount of SBEβCD. Table 2 – Comparison of Cysteine HCl and N-Acetyl-L-Cysteine with Sulfobutylether β cyclodextrin Effect of pH on Remdesivir solubility The solubility of Remdesivir was screened in a range of different acids to test the effect of pH and acidity on Remdesivir solubility. The results demonstrated in Table 3 indicate that the solubility of Remdesivir is increased at lower pH and in the presence of acids. This indicates that organic acids and other acidulants may improve the solubilization and dissolution of Remdesivir from an oral dosage form. T
In order to determine the stability of the prodrug Remdesivir at different pH, the stability of prodrug Remdesivir was tested over time at physiologically relevant pH of gastrointestinal media. The degradation of Remdesivir was determined by measuring the amount of unchanged Remdesivir using a suitable high pressure liquid chromatographic (HPLC) method and comparing the results against a pure reference sample of Remdesivir. As shown in Figure 1, the results show an acceptable stability and minimal degradation at a pH between 3 and 9. Effect of co-solvents on solubility Various co-solvents were screened for their solubilizing effect on Remdesivir, with results shown in Table 4. Table 4 The results demonstrated that solubilizing with suitable combinations of cosolvents and solubilizing excipients, it is possible to sustain the solubility of Remdesivir in various gastrointestinal media that would be encountered over the course of gastric transit and intestinal absorption following oral administration. Since only the dissolved drug substance is absorbed, the sustenance of solubility is critical for a poorly soluble and slow-dissolving molecule, such as, Remdesivir, for maximizing oral bioavailability. Similarly, the data demonstrates that certain combinations of cosolvents and solubilizing excipients may be useful for the formulation of an injectable dosage form that does not contain SBEβCD. Effect of surfactants on solubility Table 5
Remdesivir solubility was also tested in the presence of various different surfactants, with polysorbate and polyoxyl castor oil surfactants (both with a HLB value of 15) demonstrating the best results. Pharmaceutical compositions Based in part on the solubility and stability studies at different pH cited above, the present inventors developed the following Example pharmaceutical compositions. Remdesivir was found to be effectively solubilized in these example pharmaceutical compositions. Furthermore, Example Pharmaceutical composition 1 showed good results in subsequent dissolution and solubility testing. Table 6: Example Pharmaceutical composition 1 - ES040-36 Table 7: Example Pharmaceutical composition 2 - ES040-32A Table 8: Example Pharmaceutical composition 3 - ES040-86 Table 9: Example Pharmaceutical composition 4 - ES040-90 Dissolution and Solubility Study The solubility and/or dissolution of Remdesivir over time was determined for various pharmaceutical compositions using a Type II dissolution apparatus. The dissolution of the liquid formulation filled into hard-gelatin capsule and “as-is”, i.e. without being filled into the capsule shell were compared to the release of the non-formulated powder drug substance filled into the capsule, as well as the latter in combination with the solubilizing complexing agent, SBEβCD. The dissolution profiles were compared to that of acetaminophen drug substance filled into a hard-gelatin capsule. Acetaminophen has over 80% bioavailability in practice. The dissolution tests were carried out at a stirring speed of 100 rpm with 15 mg Remdesivir in 300 mL of dissolution media comprising 0.4% solution of Tween 80 in water, which had been previously determined to provide enough solubility of Remdesivir for the test dose of 15 mg. At appropriate time intervals, about 1 mL aliquots of the dissolution media were withdrawn, filtered and tested using a high-pressure chromatographic assay method for Remdesivir. The area under the peak for the drug at the standard elution time was then compared against that of an external reference standard of Remdesivir to determine the concentration of dissolved Remdesivir at any given time. Specifically, the Example formulation 1 (ES040-36) comprising Remdesivir was tested both as a solution added directly into the dissolution medium without being filled into a capsule shell to represent the release from an oral solution and also as filled into a hard-gelatin capsule. The Example formulations were compared to the solid form of the Remdesivir in a capsule containing no excipients or in the presence of the solubilizing excipient, SBEβCD, used in the currently marketed injected formulations, as a reference Example. The results of the study are shown in Figure 2. The diamond datapoints correspond to the pharmaceutical composition of the invention. The open diamonds with a dashed line represent the dissolution of the composition when it is directly added to the dissolution medium as a liquid phase without being filled into a hard-gelatin capsule; the filled diamonds with a solid line represent the dissolution of the composition when it has been filled into hard-gelatin capsule and then added to the dissolution medium. The circle datapoints with thin dashed line correspond to a different active ingredient, acetaminophen, to represent the dissolution profile of a drug with high bioavailability for comparison. The comparative control comprises powdered bulk acetaminophen drug substance filled into hard-gelatin capsule. The square datapoints represent the dissolution of Remdesivir drug substance as a powder filled into hard- gelatin capsule either with a solubilizing excipient, SBEβCD (open squares) or without any other excipient (closed squares). In the absence of pharmaceutical excipients, Remdesivir showed very slow dissolution in the dissolution medium selected to create and maintain a sink condition for the drug. The dissolution medium comprising 0.4% Tween 80 in water was predetermined to provide adequate solubility for the dose of Remdesivir selected for the dissolution test. Sink conditions ensured that there was sufficient solubility of Remdesivir in the medium to generate a concentration gradient between the saturated solution at the surface of a dissolving drug particle and the bulk of the dissolution medium so as to drive the diffusion of the drug molecules away from the dissolving particle-surface towards the bulk. Despite such sink conditions, the Remdesivir drug substance in the capsule (Figure 2; “Remdesivir in Cap”) performed much more poorly compared to the control Acetaminophen (Figure 2; “Acetaminophen API in Cap”), which has high oral bioavailability. For oral formulations of drugs with very poor solubility, such as Remdesivir, a slow-rate of dissolution would reduce the rate of absorption and rob the precious window of time available for absorption from the intestine, resulting in lower oral bioavailability. In contrast, Example formulation 1 (ES040-36) both added directly as a solution (see Figure 2, diamond datapoint with dashed line, “ES050-36 Without Capsule”) and when filled into a hard-gelatin capsule (see Figure 2, diamond datapoint with solid line, “ES050-36 in Capsule”) significantly improved the rate of dissolution and rapidly reached maximum concentration of Remdesivir in the dissolution medium. The above results demonstrate that the pharmaceutical compositions described herein can increase the solubility and dissolution rate of Remdesivir compared to the API in capsule and that with added SBEβCD – the solubilizing excipient used in currently marketed formulations. As a result, the pharmaceutical compositions described herein may be suitable for oral administration and have improved absorption in the gastrointestinal tract as compared Remdesivir alone or that in presence of SBEβCD, thereby leading to improved bioavailability. Furthermore, in the pharmaceutical compositions described herein, Remdesivir can also be easily diluted in aqueous media without the risk of precipitation, thereby, providing a strategy of administering the drug as an injection, an infusate, or as an oral solution at various concentrations to allow for accurate dosing without the need for large quantities of the solubilizing excipient, SBEβCD, that is contraindicated for very young children and in adults with impaired kidney functions. In Vivo Beagle Study An in vivo dog study in beagles was carried out to determine the pharmacokinetic (PK) profile of Remdesivir following 1) a single intravenous (IV) infusion of a control formulation and 2) an oral (PO) dose of an Example pharmaceutical composition ES040-72 according to the present invention. Table 10: Pharmaceutical composition used in beagle study - ES040-72 Table 11: Test System for the in vivo study Table 12: Dosage of Control and Example Formulations a - The Remdesivir Control Formulation (a 5 mg/mL solution) was matching to VEKLURY® (i.e. a commercially available Remdesivir formulation). This was diluted with sterile water-for injection (WFI) to 2 mg/mL. The appropriate dose (by weight) was administered by a single 30 min infusion via cerphalic vein using Medfusion 2001 syringe pumps. b - The Example Pharmaceutical Composition ES040-72 was placed in a Torpac hard gelatin capsule size # 12 (i.e.5 mL volume) for dosing. The appropriate dose volume was calculated based on the exact dose concentration. The dogs received a single Torpac capsule. Following capsule administration, a squirt of water was given orally to aid transfer of the capsule to the stomach. Plasma Collection For both IV or oral (PO) administered doses, plasma samples were collected over a period of 48 hours. Further details of the plasma collection are detailed in Table 13. Table 13: Blood Sample Collection for Plasma P rotease cocktail Instructions: a. Add 1 mL of KF Solution (4 mg/mL) [prepared by weighing 80 mg of KF and mixing with 20 mL Ultrapure deionized water], b. Dissolve 1 tablet of Complete Tablet (Mini EDTA free Easypack protease inhibitor cocktail tablet, Roche, Cat. No 04693159001), c. Mix thoroughly until tablet has dissolved, d. Add 1 mL of 25 mM EDTA Solution in water (the pH adjusted to 7 using 1N potassium hydroxide), e. Mix thoroughly, f. Store at 2-8 º C. PBMC (Peripheral Blood Mononuclear Cells) Collection For both IV or oral (PO) administered doses, blood samples were collected to determine the presence of analytes in PBMCs. Further details are detailed in Table 14. Table 14: PBMC Collection Results As indicated by Figure 3 and as demonstrated by Table 15, the oral dosage form successfully matches the systemic exposure of the key active metabolite GS-441524 between both the IV and oral administration routes. Since this same key metabolite is detected in the blood plasma following IV administration and at levels that are sustained well above those of the prodrug, Remdesivir, as reported in primate and human studies, there is evidence to suggest that GS-441524 is taken up into the target tissue and converted to the active triphosphate metabolite following phosphorylation. GS-441524 has already been shown in the literature to show considerable in vitro activity against various SARS-CoV-2 infected cell lines and the plasma concentrations of this metabolite following IV administration in vivo are consistently above its own EC50, while that of Remdesivir rapidly declines to well below its own EC50. As a result, matching exposure and plasma levels of the key metabolite following oral administration of Remdesivir, are expected to demonstrate comparable pharmacological activity as the IV infusion. The present pharmaceutical formulation and strategy of administering Remdesivir, instead of GS-441524, are nevertheless important to achieve maximum concentration and exposure of GS-441524.On its own, GS-441524, has poor oral bioavailability due to poor permeability through the intestinal membrane. Table 15: Plasma Pharmacokinetic Summary for GS-441524, i.e. Compound (C) In addition, GS-441524 (Compound (C) was detected in PBMC cells following both IV and oral (PO) administration. In Vitro Metabolism Study The Relative abundance (%) of metabolites post-incubation of Remdesivir (10 µM) was determined after culture with human hepatocytes (1.3 million cells/mL). The results are shown in Table 16. Samples were analysed by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) with a quadrople time of flight mass spectrometer, for acquisition of high-resolution accurate mass data, with electrospray ionization incorporating in-line UV detection with a photodiode array detector. Table 16: Relative abundance of analytes post-incubation with Remdesivir ND – not detected These results demonstrate that it is expected that the predominant end product of 1 st pass metabolism of Remdesivir by liver to be GS-441524, which is the same metabolite that is the predominant and sustained species in the blood plasma following intravenous (IV) administration of Remdesivir. Following IV administration, Remdesivir is converted to GS-441524 by the esterases present in the blood. Hence, these in vitro results suggest that the exposure to GS-441524 is the same as that following IV administration.
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