sofosbuvir  2014
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Proprietary Name
Active Ingredient
Dosage Form; Route
Strength
Appl No
SOVALDI
sofosbuvir
TABLET; ORAL
400MG
N204671
Approval Date
Applicant
1st Orange Book Patent
Patent Expiration
 
Dec 6, 2013
GILEAD SCIENCES INC
8334270
Mar 21, 2028
 
sofosbuvir

Description
SOVALDI is the brand name for sofosbuvir, a nucleotide analog inhibitor of HCV NS5B polymerase.

The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-
4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino) propanoate. It has a
molecular formula of C22H29FN3O9P and a molecular weight of 529.45. Sofosbuvir is a white to off-white crystalline
solid with a solubility of ≥ 2 mg/mL across the pH range of 2-7.7 at 37 oC and is slightly soluble in water.

SOVALDI tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the
following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and
microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive
ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

Indications and Dosage
SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of
chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Monotherapy of
SOVALDI is not recommended for treatment of CHC. The recommended dose of SOVALDI is one 400 mg tablet,
taken orally, once daily with or without food.

Mechanism Of Action
Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus.

Pharmacokinetics

Absorption
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been
evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of SOVALDI,
sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5-2 hour post-dose, regardless of dose
level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population
pharmacokinetic analysis in subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or
without pegylated interferon), geometric mean steady state sofosbuvir (N=838) and GS- 331007 (N=1695) AUC0-24
were 828 ng•hr/mL and 6790 ng•hr/mL, respectively. Relative to healthy subjects administered sofosbuvir alone (N =
272), the sofosbuvir AUC0-24 was 39% higher and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-
infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to
1200 mg.

Effect Of Food
Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did
not substantially affect the sofosbuvir Cmax or AUC0-inf. The exposure of GS-331007 was not altered in the
presence of a high-fat meal. Therefore, SOVALDI can be administered without regard to food.

Distribution
Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug
concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 was minimal in human plasma.
After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was
approximately 0.7.

Metabolism
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate
GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed
by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad
nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently
rephosphorylated and lacks anti-HCV activity in vitro.

After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and
> 90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic
exposure, respectively.
Elimination

Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%,
consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority
of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These
data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of
sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.

Most Common Side Effects
The most common adverse events ( ≥ 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache.
The most common adverse events ( ≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were
fatigue, headache, nausea, insomnia and anemia.

[For details, please, review product inserts (label) and discuss with your health care providers.]

___________________________________________________________________________________________

IP
T
he products are protected by five patents (as of June 15, 2014) and they are 7964580, 8334270, 8580765,          
8618076, and 8633309. And, the relevant patent applications
(as of June 15, 2014) are as follows:
20140127158
A method of treating hepatitis C virus infection, comprising administering to a subject in need
thereof (a) an effective amount of at least one HCV inhibitor selected from the group consisting of
an HCV NS3 inhibitor, an HCV NS5B inhibitor, ribavirin, and an IFN-.alpha.; and (b) an effective
amount of an anti-HCV compound of formula (I).
20140030221
20130344030
20130344029
Provided are compounds of Formula I: ##STR00001## and pharmaceutically acceptable salts
and esters thereof. The compounds, compositions, and methods provided are useful for the
treatment of virus infections, particularly hepatitis C infections.
20130309196
20130309195
20130164260
The disclosure is related to anti-viral compounds, compositions containing such compounds, and
therapeutic methods that include the administration of such compounds, as well as to processes
and intermediates useful for preparing such compounds.