Indications:
● Chronic hepatitis C
● Viral infection of liver
About Composition :
Pharmacology
Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus. It is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), Sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator. More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material.
Pharmacodynamics:
The effect of sofosbuvir 400mg (three times the recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trials in 59 healthy subjects. At a dosage three times the maximum recommended dosage, Sofosbuvir does not prolong QTc to any clinically relevant extent.
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 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 AUC0–24 was 969 ng∙hr/mL for sofosbuvir (N=838), and 6790 ng∙hr/mL for GS-331007 (N=1695).
Relative to healthy subjects administered sofosbuvir alone (N=272), the sofosbuvir AUC0–24 was 60% 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.
Protein Binding:Sofosbuvir is approximately 61- 65% bound to human plasma proteins.
Metabolism:In vitro studies in human liver microsomes showed that sofosbuvir was an efficient substrate for Cathepsin
A (Cat A) and carboxyl esterase 1 (CES1). Sofosbuvir was cleaved by CatA and CES1 and subsequent activation steps included
amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-
cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase. In vitro data indicated that Cat A
preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity.
Pregnancy & Breast Feeding:
Pregnancy
There are no well controlled studies evaluating the use of sofosbuvir during human pregnancy. In animal studies involving
rats and rabbits, no adverse effects on fetal development were observed with sofosbuvir. However, in certain patient
populations, sofosbuvir must be administered with ribavirin, which is contraindicated during pregnancy (FDA pregnancy risk
category X) and in females who may become pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Studies
of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or
embryocidal properties in all the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female patients
exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged
to report any cases to the Ribavirin Pregnancy Registry.
Breast-feeding
It is unknown whether sofosbuvir or its metabolites are excreted in human milk, affect milk production, or have an adverse
effect on nursing infants. Simeprevir may be considered as an alternative; however, its excretion into human breast milk is
also unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or
inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested
drug, health care providers are encouraged to report the adverse effect to the FDA.
Side Effects:
● Chills
● Ulcers or white spots in the mouth
● Lower back pain
● Headache
● Rash
● Irritability
● Diarrhea
● Nausea
● Decreased appetite
● Muscle pain and cramps
Storage:
Store at room temperature below 30°C.