BUVIR-LP

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

Acetone acts as a solvent and is utilized in various biochemical pathways. It participates in the biosynthesis of isopropanol and is involved in the degradation pathways where it converts into other metabolites such as methylglyoxal and acetoacetate. It also plays a role in pyruvate fermentation and is integral to the fermentation processes in Clostridium acetobutylicum.

Pharmacodynamics

Acetone has a low molecular weight and is highly volatile, which allows it to penetrate biological membranes easily. Its pharmacological effects are primarily due to its role as a solvent and its ability to influence metabolic processes. Acetone can affect lipid metabolism and may impact energy homeostasis by influencing the balance between fat and carbohydrate utilization.

Pharmacokinetics

Acetone is rapidly absorbed through inhalation and dermal exposure. It is distributed throughout the body and can cross the blood-brain barrier. Metabolism occurs primarily in the liver where acetone is converted into acetoacetate and other metabolites. The elimination of acetone occurs mainly through renal excretion, with a half-life varying based on the route of exposure and individual metabolism.

Pregnancy

Acetone is classified as a pregnancy category C drug. Its effects during pregnancy are not well-studied, and caution should be exercised.

Breast-feeding

There is limited information on the excretion of acetone in breast milk. Caution is advised when using acetone during breastfeeding.

Storage

Store in a cool, dry place, away from heat and direct sunlight. Keep tightly closed in original container.

Indications

• Chronic hepatitis C virus infection
• HCV genotype 1 infection
• HCV genotype 4, 5, or 6 infection (in combination with sofosbuvir)

Dosage

Children: Refer to specific guidelines and BNF for paediatric dosing information.

Adults: Refer to specific guidelines and BNF for precise dosing information.

Mechanism of action

Ledsipasvir is a direct-acting antiviral agent that acts as an inhibitor of the hepatitis C virus NS5A protein. This protein is essential for viral replication and assembly. By inhibiting NS5A, ledispasvir disrupts the lifecycle of the virus, preventing the production of new viral particles.

Pharmacodynamics

Ledsipasvir's antiviral activity is characterized by its ability to inhibit HCV replication. The drug is effective against various HCV genotypes, demonstrating potent antiviral effects, thus leading to significant reductions in viral RNA levels in infected patients. The combination of ledispasvir and sofosbuvir has shown high rates of sustained virologic response, indicating successful treatment outcomes.

Pharmacokinetics

Ledsipasvir is well absorbed following oral administration, with peak plasma concentrations occurring approximately 4 to 5 hours post-dose. The drug has a long half-life, allowing for once-daily dosing. It is primarily metabolized by the liver and is eliminated via the bile. Food can enhance the absorption of ledispasvir, making it advisable to take it with or without food.

Contra-indications

• Severe hepatic impairment
• Hypersensitivity to ledipasvir or any component of the formulation

Adverse effects

• Headache
• Fatigue
• Nausea
• Diarrhea
• Insomnia
• Rash

Interactions

• Caution with co-administration of drugs that are strong inducers of CYP3A
• Avoid use with certain anticonvulsants, such as carbamazepine and phenytoin
• May interact with statins and other drugs metabolized by CYP3A

Precautions

• Monitor liver function in patients with pre-existing liver disease
• Evaluate for potential drug interactions before prescribing
• Use with caution in patients with a history of significant drug allergies

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted.

Breast-feeding

It is not known whether ledipasvir is excreted in human milk. Caution should be exercised when administered to a nursing woman.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablet containing ledipasvir and sofosbuvir

Dosage

Children: Refer to the specific drug formulation and its recommended dosing guidelines for children.

Adults: Refer to the specific drug formulation and its recommended dosing guidelines.

Mechanism of action

Solvates primarily function by modifying the solubility of active pharmaceutical ingredients (APIs). They enhance the dissolution rate of poorly soluble drugs, facilitating their absorption in the gastrointestinal tract. This mechanism is essential for improving the pharmacokinetic profile of medications, allowing for more efficient release and uptake of therapeutic agents in the body.

Pharmacodynamics

The pharmacodynamics of solvates depend on the specific drug they are associated with. Generally, solvates can improve the therapeutic effects of drugs by ensuring that they reach their site of action in adequate concentrations. By enhancing solubility, solvates can lead to increased bioavailability, resulting in improved efficacy and reduced variability in drug response among patients.

Pharmacokinetics

Pharmacokinetically, solvates may alter the absorption, distribution, metabolism, and excretion (ADME) of the drug they are associated with. The solvate form can influence the rate and extent of absorption from the gastrointestinal tract, leading to faster onset of action. Additionally, the stability of the solvate can affect the drug's shelf-life and suitability for various routes of administration.

Pregnancy

There is limited data on the use of solvate during pregnancy. It is recommended to weigh the potential benefits against possible risks.

Breast-feeding

Caution is advised when using solvate during breastfeeding, as it may pass into breast milk.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

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.