Sofosbuvir
Sofosbuvir was approved by the U.S. Food and Drug Administration (FDA) on December 6, 2013. then approved by European Medicine Agency (EMA) on January 16, 2014, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on March 26, 2015. It was developed and marketed as Sovaldi® by Gilead Sciences.
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. It is indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.
Sovaldi® is available as film-coated tablet for oral use, containing 400 mg of free Sofosbuvir. The recommended dose is 400 mg once daily with or without food.
Update Date：2016-03-14
- Drug Name：
- Sofosbuvir
- Research Code：
- GS-7977; PSI-7977
- Trade Name：
- Sovaldi®
- MOA：
- HCV NS5B polymerase inhibitor
- Indication：
- HCV infection
- Status：
- Approved
- Company：
- Gilead (Originator)
- Sales：
-
$5,276 Million (Y2015);
$10,283 Million (Y2014);
$139 Million (Y2013); - ATC Code：
- J05AB
Update Date：2015-08-27
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-12-06 | Marketing approval | Sovaldi | HCV infection | Tablet, Film coated | 400 mg | Gilead | Priority |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-01-16 | Marketing approval | Sovaldi | HCV infection | Tablet, Film coated | 400 mg | Gilead |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2015-03-26 | Marketing approval | Sovaldi | HCV infection | Tablet, Film coated | 400 mg | Gilead |
Update Date：2015-08-27
|
Molecular Weight | 529.45 | ||||||||||||
| Formula | C22H29FN3O9P | |||||||||||||
| CAS No. | 1190307-88-0 (Sofosbuvir); | |||||||||||||
| Chemical Name | Propan-2-yl (2S)-2-{[(S)-{[(3R,4R,5R)-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate | |||||||||||||
| Sofosbuvir （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-09-02
Update Date：2015-11-25
Update Date：2016-06-08
Mechanism of Action
Sofosbuvir is a nucleotide analog prodrug of 2'-deoxy- 2'-C-methyluridine monophosphate that undergoes intracellular metabolism to form the pharmacologically active uridine triphosphate (GS-461203), which can inhibit HCV RNA replication.
GS-461203, which acted as a chain terminator and incorporated into HCV RNA by the NS5B polymerase,
inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a, and 4a (IC50 = 0.7-2.6 μM, and 8.5- to 24-fold for S282T substitution NS5B).
GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
Sofosbuvir showed no antiviral activity against human rhinovirus type 10 or 14, respiratory syncytial virus, influenza A virus, and HIV, at the highest tested concentration (100 μM).
The isomeric mixture GS-9851, sofosbuvir (GS-7977) and its diastereomer GS-491241 underwent hydrolysis of the carboxyl eater moiety catalyzed by human cathepsin A or carboxylesterase 1 to form the GS-566500. GS-566500 underwent phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 to form GS-606965. GS-606965 underwent high capacity nucleotide phosphorylation (uridine monophosphate-cytidine monophosphate kinase, nucleoside diphosphate kinase) pathways resulted in the formation of the pharmacologically active nucleoside analog triphosphate GS-461203. GS-606965 underwent de phosphorylation to form the GS-331007 released into circulatory system. (Figure A)
In Vitro Efficacy
Sofosbuvir inhibited HCV infection:
● GT1a-H77: EC50 = 30 nM and EC90 = 140 nM
● GT2a-JFH1: EC50 = 20 nM and EC90 = 130 nM
Sofosbuvir inhibited the HCV replicons (Genotype 1a-H77, 1b-Con1, 2a-JFH1, 3a-S52, 4a-ED43 and Genotype 1b backbone containing 2b, 5a or 6a NS5B) in cells:
● In stable replicon cells: EC50 = 14-110 nM
● In transient replication assay: EC50 = 14.4-241.7 nM
Sofosbuvir inhibited the HCV chimeric replicons (Genotype 1a, 1b, 2 and 3a) containing NS5B gene derived from 217 clinical subject isolates: Mean EC50 = 78.4 nM.
No significant effect on the activity of sofosbuvir was observed in the presence of human serum protein.
NS5B S282T substitution was observed in all 7 genotype HCV replicons (1b, 2a, 2b, 3a, 4a, 5a and 6a) when the replicon cells were treated with sofosbuvir concentrations of 10 to 30 times the wild-type EC50 value:
● The S282T substitution displayed reduced susceptibility to sofosbuvir across all 7 genotypes, fold change in EC50 to the wild type: 2.4-18
● The S282T alone substitution, fold change in EC50 values: 4-11
Sofosbuvir did not display cross-resistant to NS3/4A protease inhibitors, NS5A inhibitors and NS5B inhibitors.
Update Date：2016-06-08
Absorption of Sofosbuvir and GS-9851
Exhibited a non-linear pharmacokinetics in humans following oral dosing. The increases in Cmax and AUC appeared to be more than dose-proportional in the dose range of 100 to 400 mg sofosbuvir. The main metabolite GS-331007 appeared to be linear pharmacokinetics.
Had a low oral bioavailability in dogs (~10%) and fraction of sofosbuvir absorbed was 40%. The difference between the bioavailability and the fraction absorbed was due to the high hepatic extraction ratio of sofosbuvir (~75%).
The isomeric mixture GS-9851 (sofosbuvir and its diastereomer GS-491242) was absorbed rapidly (Tmax = 0.5 to 1 h) in dogs and monkeys. Meanwhile, sofosbuvir was also absorbed rapidly in humans (Tmax = 1 h).
The half-life of sofosbuvir was 0.54-0.75 h in humans, but the half-life of main metabolite GS-331007 was higher than sofosbuvir in humans (7.37-9.18 h), after oral administration. The half-life of GS-9851 was 0.6 h in dogs, but the half-life of GS-331007 was higher in rats (3 h), dogs (6.2 h), mice (2.3 h) and monkeys (>24 h), after oral administration.
GS-9851 had a low permeability, with the Pe = 0.46 nm/s in PAMPA monolayer model.
Distribution of Sofosbuvir
Exhibited moderate plasma protein binding in humans (61%-65%) and dogs (<70%).
Had a Cb:Cp ratio of 0.71 in humans in vivo.
In SD rats after oral administration:
● Relatively higher concentration levels were observed in large intestine, small intestine, stomach and liver, in addition, the concentrations of the alimentary canal, lymphatic and excretory systems were also high, but sofosbuvir could not cross the blood-brain barrier.
● At 48 h post-dose, sofosbuvir and related metabolites were almost completely absent from tissues.
● No remarkable differences between pigmented and non-pigmented rats were identified.
Metabolism of GS-9851
GS-9851 was stable in human plasma and whole blood, SGF, SIF, but unstable in rodent animals plasma due to high esterase activity.
GS-9851 was extensively metabolized in human liver S9 fraction.
GS-9851 was massively metabolized in the liver to form the pharmacologically active, intracellular nucleoside analog
triphosphate GS-461203 but it represented less than 5% of total GS-9851 related metabolites.
GS-331007 was the most abundant circulating metabolite (>75% of circulating plasma radioactivity) in humans and animals, but lacked activity (EC90 >78 μM) in vitro HCV replicon assays.
GS-9851 and metabolites were minimally metabolized by CYP, flavin monooxygenase (FMO), and uridine diphosphate
glucuronosyltransferase (UGT) enzymes.
The metabolic activation pathway involved sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavaged by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
Importantly, the conversion between sofosbuvir (GS-7977) and its isomeric (GS-491241) were not detected in rats, dogs, human plasma and urine.
Excretion of Sofosbuvir
Was predominantly eliminated in urine in rats, mice, dogs and humans, with GS-331007 (78% of dose in humans) as the significant component.
Drug-Drug interaction
Sofosbuvir and its metabolites had no inhibition for CYP1A2, 2C8, 2C9, 2C19 and 2D6. While sofosbuvir had weak
inhibition for CYP3A4 (IC50 = 53.1 μM).
Had no induction for CYP3A4, 2B6 and 1A2
Was a substrate of P-gp and BCRP and had no inhibition for P-gp and BCRP
Was not an inhibitor of OATP1B1/3 or OCT1
Update Date：2016-06-08
Single-Dose Toxicity
Single-dose oral administration of GS-9851 in different species:
● Rat MTD: ≥1800 mg/kg
● Dog MTD: ≥1000 mg/kg
● Major findings included GI tract, liver and heart toxicity.
Repeated-Dose Toxicity
Repeated-dose oral administration of sofosbuvir in different species from 1 to 39 weeks:
● Slight toxicity was observed in all studies.
● For rats: The NOAEL was 500 mg/kg/day.
● For dogs: The NOAEL was 100 mg/kg/day, and toxicity was mainly GI-tract toxicity.
● GS-9851 caused heart toxicity. While sofosbuvir did not.
Safety Pharmacology
No significant effects on neurologic (Irwin test) or respiratory parameters (respiratory rate, tidal or minute volumes) were observed in rats following single oral dose of GS-9851 up to 1000 mg/kg.
No significant cardiovascular effects on hemodynamic (HR and BP) or electrocardiographic parameters were noted for up to 24 h post-dose in telemetry-monitored dogs given single oral dose of GS-9851 up to 1000 mg/kg.
GS-9851 showed slight QT interval prolongation, while sofosbuvir did not.
GS-9851 and its metabolites did not significantly inhibit hERG current in vitro at up to the highest concentration tested.
Genotoxicity
Sofosbuvir was neither mutagenic nor clastogenic as tested in a standard battery of in vitro and in vivo genotoxicity assays.
Reproductive and Developmental Toxicity
Fertility and early embryo development: In rats, the NAOEL was 500 mg/kg/day since no significant effects were observed.
Embryo-fetal development: In rats, the overall NAOELs were 500 (rat) and 300 mg/kg/day (rabbit) since no significant embryo-fetal developmental or maternal adverse effects were observed.
Pre- and postnatal development: The NOAEL for maternal toxicity and the NOEL for pre- and postnatal development was 500 mg/kg/day.
Sofosbuvir was distributed in fetus and excreted into milk in lactating rats.
Carcinogenicity
Two-year carcinogenicity studies of sofosbuvir were conducted in mice (up to 200 and 600 mg/kg for males and females, respectively) and rats (up to 750 mg/kg for both males and females).
No increase in the incidence of drug-related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC exposure to the predominant circulating metabolite GS-331007 of approximately 7- and 30-fold (mouse) and 13- and 17-fold (rat) in males and females, respectively than that in humans at the recommended clinical dose.
