MAVIRET FILM-COATED TABLET 100MG/40MG

Glecaprevir
Pibrentasvir

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

(3aR,7S,10S,12R,21E,24aR)-7-tert-butyl-N-{(1R,2R)-2­ (difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl}-20,20-difluoro­ 5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1H,10H-9,12­ methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononadecino[11,12-b]quinoxaline-10­ carboxamide hydrate | Glécaprévir | glecaprevirum | Glecaprevir |

Description

Glecaprevir is a direct acting antiviral agent and Hepatitis C virus (HCV) NS3/4A protease inhibitor that targets the the viral RNA replication. In combination with [DB13878], glecaprevir is a useful therapy for patients who experienced therapeutic failure from other NS3/4A protease inhibitors. It demonstrates a high genetic barrier against resistance mutations of the virus. In cell cultures, the emergence of amino acid substitutions at NS3 resistance-associated positions A156 or D/Q168 in HCV genotype 1a, 2a or 3a replicons led to reduced susceptibility to glecaprevir [FDA Label]. The combinations of amino acid substitutions at NS3 position Y65H and D/Q168 also results in greater reductions in glecaprevir susceptibility, and NS3 Q80R in genotype 3a patients also leads to glecaprevir resistance [FDA Label]. Glecaprevir is available as an oral combination therapy with [DB13878] under the brand name Mavyret. This fixed-dose combination therapy was FDA-approved in August 2017 to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis [L940]. Mavyret is also indicated for HCV genotype 1-infected patients who have been previously treated with regimens either containing an NS5A inhibitor or an NS3/4A protease inhibitor, but not both [L940]. Hepatitis C viral infection often leads to decreased liver function and subsequent liver failure, causing a significantly negative impact on the patients' quality of life. The ultimate goal of the combination treatment is to achieve sustained virologic response (SVR) and cure the patients from the infection. In clinical trials, this combination therapy achieved SVR12 rate, or undetectable Hepatitis C for twelve or more weeks after the end of treatment, of ≥93% across genotypes 1a, 2a, 3a, 4, 5 and 6 [FDA Label].

Indication

Indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both [FDA Label].

Mechanism of Action

Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is a viral enzyme necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins [FDA Label]. These multifunctional proteins, including NS3, are essential for viral replication. The N-terminal of NS3 protein confers serine protease activity, whileThe C-terminus of NS3 encodes a DExH/D-box RNA helicase which hydyolyzes NTP as an energy source to unwind double-stranded RNA in a 3′ to 5′ direction during replication of viral genomic RNA [A20376]. NS4A is a cofactor for NS3 that directs the localization of NS3 and modulates its enzymatic activities [A20376]. Glecaprevir disrupts the intracellular processes of the viral life cycle through inhibiting the NS3/4A protease activity of cleaving downstream junctions of HCV polypeptide and proteolytic processing of mature structural proteins [A20376].

Pharmacodynamics

In a biochemical assay studying clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a, glecaprevir displayed IC50 values ranging from 3.5 to 11.3 nM that resulted in inhibition of the proteolytic activity of recombinant NS3/4A enzymes. In HCV replicon assays, glecaprevir had median EC50 values of 0.08-4.6 nM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a [FDA Label]. In a QT study, glecaprevir is not shown to prolong the QTc interval.

Pharmacokinetics

Absorption:

In healthy subjects, the time it takes to reach the peak plasma concentration (Tmax) is approximately 5 hours. The mean peak plasma concentration (Cmax) is 597ng/mL in non-cirrhotic HCV-infected subjects. Relative to fasting conditions, the consumption of meals increases the absorption of glecaprevir by 83-163% [FDA Label].

Distribution:

Not Available

Metabolism:

Glecaprevir undergoes limited secondary metabolism in vitro, predominantly by CYP3A [FDA Label].

Elimination:

The predominant route of elimination of the drug is biliary-fecal, where 92.1% of administered drug is excreted in feces and 0.7% of the drug is excreted in the urine [FDA Label].

Half-life

The elimination half life (t1/2) is approximately 6 hours [FDA Label].

Clearance

Not Available

Toxicity

Glecaprevir is not shown to be genotoxic according to *in vitro* or *in vivo* studies. It also shows to have no effect on mating, female or male fertility, or early embryonic development in rodent studies. Carcinogenicity studies with glecaprevir have not been conducted [FDA Label].

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

Pibrentasvir | Pibrentasvir |

Description

Pibrentasvir is a direct acting antiviral agent and Hepatitis C virus (HCV) NS5A inhibitor that targets the the viral RNA replication and viron assembly. In combination with [DB13879], pibrentastiv is a useful therapy for patients who experienced therapeutic failure from other NS5A inhibitors. In cell cultures, the emergence of amino acid substitutions at known NS5A inhibitor resistance-associated positions in HCV genotype 1a, 2a or 3a replicons led to reduced susceptibility and resistance to pibrentasvir [FDA Label]. These resistance-associated amino acid substitutions included Q30D/deletion, Y93D/H/N or H58D +Y93H in genotype 1a replicons, F28S + M31I or P29S + K30G in genotype 2a replicons, and Y93H in genotype 3a replicons. Individual NS5A amino acid substitutions that reduced susceptibility to pibrentasvir include M28G or Q30D in a genotype 1a replicon and P32-deletion in a genotype 1b replicon [FDA Label]. Pibrentasvir is available as an oral combination therapy with [DB13879] under the brand name Mavyret. This fixed-dose combination therapy was FDA-approved in August 2017 to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis [L940]. Mavyret is also indicated for HCV genotype 1-infected patients who have been previously treated with regimens either containing an NS5A inhibitor or an NS3/4A protease inhibitor, but not both [L940]. Hepatitis C viral infection often leads to decreased liver function and subsequent liver failure, causing a significantly negative impact on the patients' quality of life. The ultimate goal of the combination treatment is to achieve sustained virologic response (SVR) and cure the patients from the infection. In clinical trials, this combination therapy achieved SVR12 rate, or undetectable Hepatitis C for twelve or more weeks after the end of treatment, of ≥93% across genotypes 1a, 2a, 3a, 4, 5 and 6 [FDA Label].

Indication

Indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both [FDA Label].

Mechanism of Action

NS5A is a phosphoprotein that plays an essential role in replication, assembly and maturation of infectious viral proteins. The basal phosphorylated form of NS5A, which is maintained by C-terminal serine cluster, is key in ensuring its interaction with the viral capsid protein, or the core protein. By blocking this interaction, pibrentasvir inhibits the assembly of proteins and production of mature HCV particles [A20375]. NS5A also interacts with viral and cellular proteins to form the HCV replicase complex, and supports the RNA replication of HCV [A20374].

Pharmacodynamics

Pibrentasvir is a pan-genotypic . According to HCV replicon assays, pibrentasvir has EC50 values ranging from 0.08-4.6 nM agaisnt laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a, or EC50 values of 0.5-4.3 pM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4b, 4d, 5a, 6a, 6e and 6p [FDA Label]. It is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that confers resistance and decreased therapeutic response from other NS5A inhibitors, inluding positions 24, 28, 30, 31, 58, 92, or 93 in NS5A [FDA Label, A20374]. In a QT study, pibrentasvir is not shown to prolong the QTc interval.

Pharmacokinetics

Absorption:

In healthy subjects, the time it takes to reach the peak plasma concentration (Tmax) is approximately 5 hours. The mean peak plasma concentration (Cmax) is 110ng/mL in non-cirrhotic HCV-infected subjects. Relative to fasting conditions, the consumption of meals increases the absorption of pibrentasvir by 40-53% [FDA Label].

Distribution:

Not Available

Metabolism:

Pibrentasvir is not metabolized [FDA Label].

Elimination:

The predominant route of elimination of the drug is biliary-fecal, where 96.6% of administered drug is excreted in feces and 0% of the drug is excreted in the urine [FDA Label].

Half-life

The elimination half life (t1/2) is approximately 13 hours [FDA Label].

Clearance

Not Available

Toxicity

Pibrentasvir is not shown to be genotoxic according to *in vitro* or *in vivo* studies. It also shows to have no effect on mating, female or male fertility, or early embryonic development in rodent studies. Carcinogenicity studies with pibrentasvir have not been conducted [FDA Label].

References

  1. Health Science Authority of Singapore - Reclassified POM
  2. Drugbank

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Approval Information

MAVIRET FILM-COATED TABLET 100MG/40MG was registered with Health Science Authority of Singapore by ABBVIE PTE LTD. It is marketed with the registration number of SIN15603P with effective from 2018-12-26.

This product contains 100mg of Glecaprevir, and 40mg of Pibrentasvir in the form of TABLET, FILM COATED.

The medicine was manufactured by AbbVie Deutschland GmbH & Co. KG (Extrudate in GERMANY, and Primary and Secondary Packager) in IRELAND

It is a Presciption Only Medicine which can only be obtained from a doctor or a dentist, or from a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Anatomical Therapeutic Chemical (ATC) Classification

ATC Code: J05AP57

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