Identification

Name
Pibrentasvir
Accession Number
DB13878
Type
Small Molecule
Groups
Approved, Investigational
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 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].

Structure
Thumb
Synonyms
Not Available
External IDs
A-1325912.0 / ABT 530 / ABT-530
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
MaviretPibrentasvir (40 mg) + Glecaprevir (100 mg)TabletOralAbbvie2017-09-13Not applicableCanada
MavyretPibrentasvir (40 mg/1) + Glecaprevir (100 mg/1)Tablet, film coatedOralAbbvie2017-08-03Not applicableUs
Categories
UNII
2WU922TK3L
CAS number
1353900-92-1
Weight
Average: 1113.201
Monoisotopic: 1112.490699908
Chemical Formula
C57H65F5N10O8
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
(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)-2-{[hydroxy(methoxy)methylidene]amino}-3-methoxybutanoyl]pyrrolidin-2-yl]-1H-1,3-benzodiazol-5-yl}pyrrolidin-2-yl]-6-fluoro-1H-1,3-benzodiazol-2-yl}pyrrolidin-1-yl]-2-{[hydroxy(methoxy)methylidene]amino}-3-methoxybutan-1-one
SMILES
[H][C@](C)(OC)[C@]([H])(N=C(O)OC)C(=O)N1CCC[C@@]1([H])C1=NC2=C(N1)C=C(F)C(=C2)[C@@]1([H])CC[C@@]([H])(N1C1=CC(F)=C(N2CCC(CC2)C2=CC=C(F)C=C2)C(F)=C1)C1=CC2=C(NC(=N2)[C@]2([H])CCCN2C(=O)[C@@]([H])(N=C(O)OC)[C@@]([H])(C)OC)C=C1F

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].

Associated Conditions
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]. 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 (NS5A)
inhibitor
Hepatitis C Virus (HCV)
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
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].

Affected organisms
  • Hepatitis C Virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirThe metabolism of Abacavir can be decreased when combined with Pibrentasvir.
AbemaciclibThe serum concentration of Pibrentasvir can be increased when it is combined with Abemaciclib.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Pibrentasvir.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Pibrentasvir.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Pibrentasvir.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Pibrentasvir.
AlbendazoleThe serum concentration of Pibrentasvir can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Aldosterone can be increased when it is combined with Pibrentasvir.
AlectinibThe serum concentration of Pibrentasvir can be increased when it is combined with Alectinib.
AlitretinoinThe serum concentration of Alitretinoin can be increased when it is combined with Pibrentasvir.
Food Interactions
Not Available

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. [PubMed:28193664]
  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. [PubMed:18524832]
  3. FDA Press Announcements: FDA approves Mavyret for Hepatitis C [Link]
External Links
PubChem Compound
58031952
PubChem Substance
347829329
ChemSpider
35013016
ChEMBL
CHEMBL3545123
Wikipedia
Pibrentasvir
FDA label
Download (925 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHepatic Impairment1
1CompletedBasic ScienceImpaired Renal Function1
2Active Not RecruitingDiagnosticHepatitis C Viral Infection1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Hepatitis C Virus (HCV) Infection3
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Compensated liver disease / Hepatitis C Virus (HCV) Infection1
2RecruitingTreatmentHepatitis C Viral Infection1
2, 3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Hepatitis C Virus (HCV) Infection1
3Active Not RecruitingTreatmentChronic Hepatitis C Virus / Hepatitis C Virus (HCV) Infection1
3Active Not RecruitingTreatmentHepatitis C Viral Infection / Hepatitis C Virus (HCV) Infection1
3Active Not RecruitingTreatmentHepatitis C Virus (HCV) Infection3
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Genotype 5 or 6 Infection / Hepatitis C Virus (HCV) Infection1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Genotype 3 Hepatitis C Virus / Hepatitis C Virus (HCV) Infection1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Hepatitis C Virus (HCV) Infection2
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Compensated liver disease / Hepatitis C Virus Infection1
3CompletedTreatmentChronic Hepatitis C Virus / Hepatitis C Virus (HCV) Infection1
3CompletedTreatmentHepatitis C Virus (HCV) Infection2
3Enrolling by InvitationTreatmentHepatitis C Virus (HCV) Infection / Hepatitis C Virus Infection1
3RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / Hepatitis C Virus (HCV) Infection1
3RecruitingTreatmentHepatitis C Virus (HCV) Infection1
3RecruitingTreatmentHepatitis C, Acute1
4CompletedTreatmentHepatitis C Virus (HCV) Infection1
4Not Yet RecruitingPreventionHepatitis C Viral Infection / Kidney Diseases / Renal Failure1
Not AvailableAvailableNot AvailableHepatitis C Virus Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9586978No2010-06-102030-06-10Us
US8648037No2012-01-192032-01-19Us
US9321807No2015-06-052035-06-05Us
US8937150No2012-05-182032-05-18Us
US10039754No2010-06-102030-06-10Us
US10028937No2010-06-102030-06-10Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<0.1 mg/mLFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.00538 mg/mLALOGPS
logP5.89ALOGPS
logP6.93ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)3.58ChemAxon
pKa (Strongest Basic)5.34ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count14ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area206.56 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity286.42 m3·mol-1ChemAxon
Polarizability114.93 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

Taxonomy

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
show 10 more
Substituents
Alpha-amino acid amide / Phenylpiperidine / 1-phenylpyrrolidine / 2-phenylpyrrolidine / Alpha-amino acid or derivatives / Benzimidazole / N-acylpyrrolidine / Dialkylarylamine / Aniline or substituted anilines / Aralkylamine
show 32 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

1. Nonstructural Protein 5A (NS5A)
Kind
Protein
Organism
Hepatitis C Virus (HCV)
Pharmacological action
Yes
Actions
Inhibitor

Enzymes

Kind
Protein group
Organism
Human
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:
Kind
Protein
Organism
Human
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
Human
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
Human
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
Human
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
Human
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 09:29 / Updated on November 02, 2018 07:47