Pibrentasvir

Identification

Summary

Pibrentasvir is a Hepatitis C NS5A inhibitor used to treat Hepatitis C.

Brand Names
Maviret, Mavyret
Generic Name
Pibrentasvir
DrugBank Accession Number
DB13878
Background

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 Glecaprevir, 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 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 Label.

Pibrentasvir is available as an oral combination therapy with Glecaprevir 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 3. 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 3. 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 Label.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 1113.201
Monoisotopic: 1112.490699908
Chemical Formula
C57H65F5N10O8
Synonyms
  • Pibrentasvir
External IDs
  • A-1325912.0
  • ABT 530
  • ABT-530

Pharmacology

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 Label.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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 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 Label,1. In a QT study, pibrentasvir is not shown to prolong the QTc interval.

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 2. NS5A also interacts with viral and cellular proteins to form the HCV replicase complex, and supports the RNA replication of HCV 1.

TargetActionsOrganism
ANonstructural protein 5A
inhibitor
Hepatitis C Virus
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% Label.

Volume of distribution

Not Available

Protein binding

Pibrentasvir is >99.9% bound to human plasma proteins. The Blood-to-plasma ratio is approximately 0.62 Label.

Metabolism

Pibrentasvir is not metabolized Label.

Route of 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 Label.

Half-life

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

Clearance

Not Available

Adverse Effects
Adverseeffects
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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 Label.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirThe metabolism of Abacavir can be decreased when combined with Pibrentasvir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Pibrentasvir.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Pibrentasvir.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Pibrentasvir.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Pibrentasvir.
AlectinibAlectinib may decrease the excretion rate of Pibrentasvir which could result in a higher serum level.
AllopurinolPibrentasvir may decrease the excretion rate of Allopurinol which could result in a higher serum level.
AlpelisibThe serum concentration of Alpelisib can be increased when it is combined with Pibrentasvir.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Pibrentasvir.
AmiodaroneThe serum concentration of Pibrentasvir can be increased when it is combined with Amiodarone.
Interactions
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Food Interactions
  • Avoid St. John's Wort. Co-administration may lead to decreased serum concentrations of pibrentasvir.
  • Take with food.

Products

Products2
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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
MaviretPibrentasvir (40 mg) + Glecaprevir (100 mg)TabletOralAbbvie2017-09-13Not applicableCanada flag
MaviretPibrentasvir (40 mg) + Glecaprevir (100 mg)Tablet, film coatedOralAbb Vie Deutschland Gmb H Co. Kg2020-12-16Not applicableEU flag
MAVİRET 100 MG/40 MG FİLM KAPLI TABLET, 84 ADETPibrentasvir (40 mg) + Glecaprevir (100 mg)Tablet, coatedOralABBVİE TIBBİ İLAÇLAR SAN. VE TİC. LTD. ŞTİ.2020-08-14Not applicableTurkey flag
MavyretPibrentasvir (40 mg/1) + Glecaprevir (100 mg/1)Tablet, film coatedOralAbbVie Inc.2017-08-03Not applicableUS flag
MavyretPibrentasvir (20 mg/1) + Glecaprevir (50 mg/1)PelletOralAbbVie Inc.2021-06-10Not applicableUS flag

Categories

ATC Codes
J05AP57 — Glecaprevir and pibrentasvir
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Phenylpiperidines
Direct Parent
Phenylpiperidines
Alternative Parents
Alpha amino acid amides / Phenylpyrrolidines / Benzimidazoles / Aniline and substituted anilines / N-acylpyrrolidines / Dialkylarylamines / Aralkylamines / Fluorobenzenes / Aryl fluorides / Tertiary carboxylic acid amides
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Substituents
1-phenylpyrrolidine / 2-phenylpyrrolidine / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amine / Amino acid or derivatives / Aniline or substituted anilines / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride
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Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Hepatitis C Virus

Chemical Identifiers

UNII
2WU922TK3L
CAS number
1353900-92-1
InChI Key
VJYSBPDEJWLKKJ-NLIMODCCSA-N
InChI
InChI=1S/C57H65F5N10O8/c1-29(77-3)49(67-56(75)79-5)54(73)70-19-7-9-47(70)52-63-41-25-35(37(59)27-43(41)65-52)45-15-16-46(72(45)34-23-39(61)51(40(62)24-34)69-21-17-32(18-22-69)31-11-13-33(58)14-12-31)36-26-42-44(28-38(36)60)66-53(64-42)48-10-8-20-71(48)55(74)50(30(2)78-4)68-57(76)80-6/h11-14,23-30,32,45-50H,7-10,15-22H2,1-6H3,(H,63,65)(H,64,66)(H,67,75)(H,68,76)/t29-,30-,45-,46-,47+,48+,49+,50+/m1/s1
IUPAC Name
methyl N-[(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-{6-fluoro-2-[(2S)-1-[(2S,3R)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl]pyrrolidin-2-yl]-1H-1,3-benzodiazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-1,3-benzodiazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl]carbamate
SMILES
CO[C@H](C)[C@H](NC(=O)OC)C(=O)N1CCC[C@H]1C1=NC2=C(N1)C=C(F)C(=C2)[C@H]1CC[C@@H](N1C1=CC(F)=C(N2CCC(CC2)C2=CC=C(F)C=C2)C(F)=C1)C1=CC2=C(NC(=N2)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C=C1F

References

General References
  1. Ng TI, Krishnan P, Pilot-Matias T, Kati W, Schnell G, Beyer J, Reisch T, Lu L, Dekhtyar T, Irvin M, Tripathi R, Maring C, Randolph JT, Wagner R, Collins C: In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir. Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e02558-16. doi: 10.1128/AAC.02558-16. Print 2017 May. [Article]
  2. Masaki T, Suzuki R, Murakami K, Aizaki H, Ishii K, Murayama A, Date T, Matsuura Y, Miyamura T, Wakita T, Suzuki T: Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J Virol. 2008 Aug;82(16):7964-76. doi: 10.1128/JVI.00826-08. Epub 2008 Jun 4. [Article]
  3. FDA Press Announcements: FDA approves Mavyret for Hepatitis C [Link]
PubChem Compound
58031952
PubChem Substance
347829329
ChemSpider
35013016
RxNav
1940636
ChEMBL
CHEMBL3545123
Wikipedia
Pibrentasvir
FDA label
Download (925 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingPreventionHepatitis C Virus (HCV) Infection / Renal Failure, Chronic Renal Failure1
4Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / Chronic Kidney Disease (CKD)1
4CompletedTreatmentEnd Stage Renal Disease (ESRD) / Hepatitis C Virus (HCV) Infection1
4Enrolling by InvitationPreventionHepatitis C Virus (HCV) Infection / Respiratory Failure1
4Enrolling by InvitationTreatmentEnd Stage Renal Disease (ESRD) / Hepatitis C Virus (HCV) Infection1
4RecruitingBasic ScienceCardiovascular Disease (CVD) / Hepatitis C Virus (HCV) Infection / Human Immunodeficiency Virus (HIV) Infections1
4RecruitingTreatmentChronic Kidney Disease (CKD) / Hepatitis C Virus (HCV) Infection / Kidney Failure1
4RecruitingTreatmentHeart Transplant Infection / Hepatitis C Virus (HCV) Infection / Transplanted Kidney Complication1
4RecruitingTreatmentHepatitis C Virus (HCV) Infection1
4Unknown StatusTreatmentAddict Heroin / Hepatitis C Virus (HCV) Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, coatedOral
PelletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9586978Yes2017-03-072030-12-10US flag
US8648037Yes2014-02-112032-07-19US flag
US9321807Yes2016-04-262035-12-05US flag
US8937150Yes2015-01-202032-11-18US flag
US10039754Yes2018-08-072030-12-10US flag
US10028937Yes2018-07-242030-12-10US flag
US10286029Yes2019-05-142034-09-14US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<0.1 mg/mLFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.00557 mg/mLALOGPS
logP5.95ALOGPS
logP7.63ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)10.66ChemAxon
pKa (Strongest Basic)5.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area199.58 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity284.83 m3·mol-1ChemAxon
Polarizability113.13 Å3ChemAxon
Number of Rings10ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Hepatitis C Virus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Not Available
Gene Name
NS5A
Uniprot ID
Q5L478
Uniprot Name
Nonstructural protein 5A
Molecular Weight
48598.34 Da

Enzymes

Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. FDA Approved Drug Products: Mavyrettm (glecaprevir and pibrentasvir) tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da

Drug created on August 31, 2017 15:29 / Updated on February 21, 2021 18:54