MYHEP

Indications

• Chronic hepatitis C infection
• HCV genotype 1, 2, 3, 4, 5, or 6
• Treatment in combination with ribavirin or ledipasvir

Dosage

Adults: The typical adult dose for

Mechanism of action

Sofosbuvir is a nucleotide analog that inhibits HCV NS5B RNA-dependent RNA polymerase. It is metabolized intracellularly to the active uridine analog triphosphate, which incorporates into HCV RNA and acts as a chain terminator. By binding to the two Mg2+ ions in the active site of NS5B, sofosbuvir prevents the replication of HCV genetic material. This mechanism effectively halts viral replication, making sofosbuvir a crucial component in the treatment of HCV.

Pharmacodynamics

Sofosbuvir is known for its high efficacy against different genotypes of HCV, functioning as a pan-genotypic polymerase inhibitor. It does not exhibit significant prolongation of QTc interval at doses up to three times the standard recommendation. Its antiviral activity is primarily through the inhibition of viral replication, which is critical for the management of chronic hepatitis C.

Pharmacokinetics

Sofosbuvir is administered orally and undergoes extensive hepatic metabolism, primarily by the enzyme uridine 5′-triphosphate (UTP) to its active form. The pharmacokinetic profile indicates a half-life of about 24 hours, allowing for once-daily dosing. The drug is primarily excreted via the kidneys, and its pharmacokinetics may be influenced by factors such as liver function and co-administration with other drugs. It is advised to monitor patients closely for potential drug interactions that may affect sofosbuvir's efficacy.

Adverse effects

• Alopecia
• Anaemia
• Anxiety
• Decreased appetite
• Arthralgia
• Asthenia
• Chest pain
• Chills
• Concentration impaired
• Constipation
• Cough
• Depression
• Diarrhoea
• Dizziness
• Dry mouth
• Dyspnoea
• Fever
• Gastrointestinal discomfort
• Gastrooesophageal reflux disease
• Headaches
• Influenza-like illness
• Insomnia
• Irritability
• Memory loss
• Muscle complaints

Interactions

• Carbamazepine (severe, decreases exposure)
• St. John's Wort (severe, decreases exposure)
• Amiodarone (unknown, increases risk of severe bradycardia or heart block)
• Tipranavir (unknown, decreases exposure)
• Modafinil (unknown, decreases exposure)
• Rifampicin (unknown, decreases exposure)
• Antiarrhythmics (unknown, increases risk of severe bradycardia or heart block)

Precautions

• Monitor glucose levels closely in diabetic patients during treatment
• Avoid in pregnancy due to limited information
• Avoid in breastfeeding as present in milk in animal studies

Pregnancy

Manufacturer advises to avoid due to limited information available.

Breast-feeding

Manufacturer advises to avoid as sofosbuvir is present in milk in animal studies.

Storage

Dispense in original container (contains desiccant).

Formulations

• Ledipasvir 45 mg, Sofosbuvir 200 mg (Harvoni 45mg/200mg tablets)
• Ledipasvir 90 mg, Sofosbuvir 400 mg (Harvoni 90mg/400mg tablets)

Mechanism of action

Sofosbuvir 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 [synthesis, A7533]. 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. Sofosbuvir is a direct-acting antiviral agent (pan-genotypic polymerase inhibitor) against the hepatitis C virus. HCV RNA replication is mediated by a membrane-associated multiprotein replication complex. The HCV polymerase (NS5B protein) is an RNA-dependent RNA polymerase (RdRp). It is the essential initiating and catalytic subunit of this replication complex and is critical for the viral replication cycle. There is no human homolog for HCV NS5B RdRp. Sofosbuvir is a monophosphorylated pyrimidine nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203). GS-461203 competes with natural nucleotides for incorporation (by HCV NS5B) into the nascent RNA strand during replication of the viral genome. GS-461203 differs from endogenous pyrimidine nucleotides in that it has been modified at the 2' position with the addition of a methyl and a fluoro functional group. Incorporation of GS-461203 into nascent RNA strongly reduces the efficiency of further RNA elongation by RdRp, resulting in premature termination of RNA synthesis. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

Pharmacodynamics

Sofosbuvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA). At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.