Paritaprevir

Identification

Summary

Paritaprevir is a direct acting antiviral agent used in combination with other antiviral agents for the treatment of Hepatitis C Virus (HCV) infections.

Brand Names

Viekira Pak

Generic Name

Paritaprevir

DrugBank Accession Number

DB09297

Background

Paritaprevir is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients ⁸. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as paritaprevir. As a newer generation and directly acting HCV antiviral, paritaprevir products have better Sustained Virological Response (SVR) rates, higher barriers to resistance, fewer side effects, and a reduced pill burden compared to older agents such as Boceprevir, Telaprevir, Peginterferon alfa-2a, Peginterferon alfa-2b, and Ribavirin. By combining multiple antiretroviral medications into fixed dose products, the viral lifecycle can be targeted at multiple stages while simultaneously reducing the risk of developing resistant viral strains ⁷. Within Canada and the United States, paritaprevir is currently available in three fixed dose products: Viekira Pak (FDA), Technivie (FDA and Health Canada), and Holkira Pak (Health Canada).

More specifically, paritaprevir prevents viral replication by inhibiting the NS3/4A serine protease of Hepatitis C Virus (HCV) ^Label. Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving genetic material into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B ⁶. By inhibiting viral protease NS3/4A, paritaprevir therefore prevents viral replication and function.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Paritaprevir as a first line therapy option when used in combination with other antivirals for genotypes 1a, 1b, and 4⁸. Depending on the genotype, Paritaprevir is often used in combination with other antivirals such as Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin, with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality ⁴. Treatment with direct acting antivirals such as paritaprevir is associated with very minimal side effects, with the most common being headache and fatigue ^Label. Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects ⁵.

Paritaprevir first came on the market as a fixed-dose combination product with Ombitasvir, Dasabuvir, and Ritonavir as the FDA-approved product Viekira Pak. First approved in December 2014, Viekira Pak is indicated for the treatment of HCV genotype 1b without cirrhosis or with compensated cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a without cirrhosis or with compensated cirrhosis.

Paritaprevir is also available as a fixed-dose combination product with Ombitasvir and Ritonavir as the FDA- and Health Canada-approved product Technivie. First approved in July 2015, Technivie is indicated in combination with Ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis.

In Canada, paritaprevir is also available as a fixed-dose combination product with Ombitasvir, Dasabuvir, and Ritonavir as the Health Canada-approved, commercially available product Holkira Pak. First approved in January 2015, Holkira Pak is indicated for the treatment of HCV genotype 1b with or without cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a with or without cirrhosis.

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Paritaprevir (DB09297)

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Weight

Average: 765.89
Monoisotopic: 765.294467927

Chemical Formula

C₄₀H₄₃N₇O₇S

Synonyms

• (2R,6S,12Z,13aR,14aR,16aS)-N-(cyclopropanesulfonyl)-6-[(5-methylpyrazine-2-carbonyl)amino]-5,16-dioxo-2-[(phenanthridin-6-yl)oxy]-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide
• Paritaprevir
• Veruprevir

External IDs

• ABT 450
• ABT-450
• ABT450

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Pharmacology

Indication

When used within the fixed-dose combination product with Ombitasvir, Dasabuvir, and Ritonavir as the FDA-approved product Viekira Pak, paritaprevir is indicated for the treatment of HCV genotype 1b without cirrhosis or with compensated cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a without cirrhosis or with compensated cirrhosis.

When used within the fixed-dose combination product with Ombitasvir and Ritonavir as the FDA- and Health Canada-approved product Technivie, paritaprevir is indicated in combination with Ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis.

When used within the fixed-dose combination product with Ombitasvir, Dasabuvir, and Ritonavir as the Health Canada-approved, commercially available product Holkira Pak, paritaprevir is indicated for the treatment of HCV genotype 1b with or without cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a with or without cirrhosis.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	With compensated cirrhosis chronic hepatitis c genotype 1a	Regimen in combination with: Ombitasvir (DB09296), Dasabuvir (DB09183), Ritonavir (DB00503), Ribavirin (DB00811)	••••••••••••
Used in combination to treat	With compensated cirrhosis chronic hepatitis c genotype 1b	Combination Product in combination with: Ombitasvir (DB09296), Ritonavir (DB00503), Dasabuvir (DB09183)	••••••••••••
Used in combination to treat	Without cirrhosis chronic hepatitis c genotype 1a	Regimen in combination with: Ritonavir (DB00503), Dasabuvir (DB09183), Ribavirin (DB00811), Ombitasvir (DB09296)	••••••••••••
Used in combination to treat	Without cirrhosis chronic hepatitis c genotype 1b	Combination Product in combination with: Dasabuvir (DB09183), Ritonavir (DB00503), Ombitasvir (DB09296)	••••••••••••
Used in combination to treat	Without cirrhosis chronic hepatitis c genotype 4	Regimen in combination with: Ribavirin (DB00811), Ombitasvir (DB09296), Ritonavir (DB00503)	••••••••••••

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Pharmacodynamics

At concentrations approximately 6 and 1.8 times the therapeutic concentrations of paritaprevir and ombitasvir, the combination did not prolong QTc to any clinically relevant extent ^Label.

Mechanism of action

Paritaprevir is a potent inhibitor of the NS3/4A serine protease of Hepatitis C Virus (HCV) ^Label. Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving it into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B. By inhibiting viral protease NS3/4A, paritaprevir therefore prevents viral replication and function.

Target	Actions	Organism
ANS3/4A protein	inhibitor	Hepatitis C Virus

Absorption

Tmax of approximately 4 to 5 hours with a maximum concentration (Cmax) of 194 ng/mL ^Label.

Volume of distribution

Volume of distribution at steady state is approximately 103 L ^Label.

Protein binding

97 to 98.6% bound to human plasma proteins ^Label.

Metabolism

Paritaprevir is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5 ^Label.

Route of elimination

Following a single dose administration of 14C-paritaprevir co-dosed with 100 mg of ritonavir, approximately 88% of the radioactivity was recovered in feces with limited radioactivity (8.8%) in urine; unchanged paritaprevir accounted for 1.1% of the radioactivity in the feces and 0.05% in the urine ^Label.

Half-life

5.5 hr ^Label

Clearance

Not Available

Adverse Effects

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Toxicity

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abacavir	The metabolism of Abacavir can be decreased when combined with Paritaprevir.
Abametapir	The serum concentration of Paritaprevir can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Paritaprevir can be increased when combined with Abatacept.
Abemaciclib	Paritaprevir may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Abrocitinib	The serum concentration of Paritaprevir can be increased when it is combined with Abrocitinib.

Food Interactions

• Avoid St. John's Wort.
• Take with food.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Paritaprevir dihydrate	HRQ5901O78	1456607-71-8	AWGQIDLXYMGEEH-RHSIAEQTSA-N

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Holkira Pak	Paritaprevir (75 mg) + Dasabuvir sodium monohydrate (250 mg) + Ombitasvir (12.5 mg) + Ritonavir (50 mg)	Kit; Tablet	Oral	Abbvie	2015-01-06	2018-08-15
Technivie	Paritaprevir dihydrate (75 mg/1) + Ombitasvir heminonahydrate (12.5 mg/1) + Ritonavir (50 mg/1)	Tablet	Oral	AbbVie Inc.	2015-07-24	2019-03-14
Technivie	Paritaprevir (75 mg) + Ombitasvir (12.5 mg) + Ritonavir (50 mg)	Tablet	Oral	Abbvie	2015-11-24	2018-07-30
Viekira Pak	Paritaprevir dihydrate (75 mg/1) + Dasabuvir sodium monohydrate (250 mg/1) + Ombitasvir heminonahydrate (12.5 mg/1) + Ritonavir (50 mg/1)	Kit; Tablet, film coated	Oral	AbbVie Inc.	2014-12-19	Not applicable
VIEKIRA PAK TABLET	Paritaprevir (75 mg) + Dasabuvir (250 mg) + Ombitasvir (12.5 mg) + Ritonavir (50 mg)	Tablet, film coated	Oral	ABBVIE PTE. LTD.	2015-11-02	Not applicable

Categories

ATC Codes

J05AP53 — Ombitasvir, paritaprevir and ritonavir

• J05AP — Antivirals for treatment of HCV infections
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

J05AP52 — Dasabuvir, ombitasvir, paritaprevir and ritonavir

• J05AP — Antivirals for treatment of HCV infections
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Amides
• Amino Acids
• Amino Acids, Cyclic
• Amino Acids, Peptides, and Proteins
• Antiinfectives for Systemic Use
• Antiviral Agents
• Antivirals for Systemic Use
• Antivirals for treatment of HCV infections
• BCRP/ABCG2 Inhibitors
• Cycloparaffins
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 Substrates
• Direct Acting Antivirals
• HCV NS3/4A Protease Inhibitors
• Imino Acids
• Lactams
• NS3/4A Protease Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B1/SLCO1B1 Substrates
• OATP1B3 inhibitors
• OATP1B3 substrates
• Organic Anion Transporting Polypeptide 1B1 Inhibitors
• Organic Anion Transporting Polypeptide 1B3 Inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• Sulfones
• Sulfur Compounds
• Treatments for Hepatitis C
• UGT1A1 Inhibitors

Classification

Not classified

Affected organisms

• Hepatitis C Virus

Chemical Identifiers

UNII

OU2YM37K86

CAS number

1216941-48-8

InChI Key

UAUIUKWPKRJZJV-QPLHLKROSA-N

InChI

InChI=1S/C40H43N7O7S/c1-24-21-42-33(22-41-24)35(48)43-32-16-6-4-2-3-5-11-25-20-40(25,39(51)46-55(52,53)27-17-18-27)45-36(49)34-19-26(23-47(34)38(32)50)54-37-30-14-8-7-12-28(30)29-13-9-10-15-31(29)44-37/h5,7-15,21-22,25-27,32,34H,2-4,6,16-20,23H2,1H3,(H,43,48)(H,45,49)(H,46,51)/b11-5-/t25-,26-,32+,34+,40-/m1/s1

IUPAC Name

(1S,4R,6S,7Z,14S,18R)-N-(cyclopropanesulfonyl)-14-(5-methylpyrazine-2-amido)-2,15-dioxo-18-(phenanthridin-6-yloxy)-3,16-diazatricyclo[14.3.0.0^{4,6}]nonadec-7-ene-4-carboxamide

SMILES

[H][C@@]12C[C@]1(NC(=O)[C@]1([H])C[C@H](CN1C(=O)[C@H](CCCCC\C=C/2)NC(=O)C1=CN=C(C)C=N1)OC1=NC2=C(C=CC=C2)C2=C1C=CC=C2)C(=O)NS(=O)(=O)C1CC1

References

General References

1. Klibanov OM, Gale SE, Santevecchi B: Ombitasvir/paritaprevir/ritonavir and dasabuvir tablets for hepatitis C virus genotype 1 infection. Ann Pharmacother. 2015 May;49(5):566-81. doi: 10.1177/1060028015570729. Epub 2015 Feb 13. [Article]
2. Hull MW, Yoshida EM, Montaner JS: Update on Current Evidence for Hepatitis C Therapeutic Options in HCV Mono-infected Patients. Curr Infect Dis Rep. 2016 Jul;18(7):22. doi: 10.1007/s11908-016-0527-8. [Article]
3. Lam JT, Salazar L: New combination antiviral for the treatment of hepatitis C. Am J Health Syst Pharm. 2016 Jul 15;73(14):1042-50. doi: 10.2146/ajhp150163. Epub 2016 May 23. [Article]
4. Myers RP, Shah H, Burak KW, Cooper C, Feld JJ: An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015 Jan-Feb;29(1):19-34. Epub 2015 Jan 13. [Article]
5. Dusheiko G: Side effects of alpha interferon in chronic hepatitis C. Hepatology. 1997 Sep;26(3 Suppl 1):112S-121S. [Article]
6. Moradpour D, Penin F: Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol. 2013;369:113-42. doi: 10.1007/978-3-642-27340-7_5. [Article]
7. Bagaglio S, Uberti-Foppa C, Morsica G: Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use. Drugs. 2017 May 12. doi: 10.1007/s40265-017-0753-x. [Article]
8. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]

External Links

KEGG Drug

D10580

PubChem Compound

68498031

PubChem Substance

310265189

ChemSpider

32700634

RxNav

1597373

ChEBI

85188

ChEMBL

CHEMBL3391662

ZINC

ZINC000197964623

PharmGKB

PA166163410

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Paritaprevir

FDA label

Download (6.48 MB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Hepatitis C Virus (HCV) Infection	1
4	Completed	Prevention	Hepatitis C Virus (HCV) Infection	1
4	Completed	Treatment	Chronic Hepatitis C Virus (HCV) Infection	3
4	Completed	Treatment	Chronic Hepatitis C Virus (HCV) Infection / Chronic Kidney Disease (CKD)	1
4	Completed	Treatment	End Stage Renal Disease (ESRD) / HCV Coinfection	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral
Kit; tablet, film coated	Oral
Tablet, film coated	Oral	250 mg
Kit; tablet	Oral
Tablet, film coated	Oral
Tablet, coated	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US6703403	Yes	2004-03-09	2016-12-26
US6037157	Yes	2000-03-14	2016-12-26
US7364752	Yes	2008-04-29	2021-05-10
US7148359	Yes	2006-12-12	2020-01-19
US8268349	Yes	2012-09-18	2025-02-25
US8399015	Yes	2013-03-19	2025-02-25
US9139536	No	2015-09-22	2028-11-09
US8685984	No	2014-04-01	2032-09-04
US8466159	No	2013-06-18	2032-09-04
US8642538	No	2014-02-04	2029-09-10
US8501238	No	2013-08-06	2028-09-17
US8680106	No	2014-03-25	2032-09-04
US8492386	No	2013-07-23	2032-09-04
US8188104	No	2012-05-29	2029-05-17
US9006387	No	2015-04-14	2030-06-10
US9044480	No	2015-06-02	2031-04-10
US8686026	No	2014-04-01	2031-06-09
US8420596	Yes	2013-04-16	2031-10-10
US8691938	No	2014-04-08	2032-04-13
US9629841	No	2017-04-25	2033-10-18
US9333204	No	2016-05-10	2035-01-02
US9744170	No	2017-08-29	2035-01-02
US10105365	No	2018-10-23	2035-01-02
US10201584	No	2019-02-12	2032-05-17
US10201542	No	2019-02-12	2033-10-18
US10201541	No	2019-02-12	2032-05-17

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00778 mg/mL	ALOGPS
logP	3.5	ALOGPS
logP	2.49	Chemaxon
logS	-5	ALOGPS
pKa (Strongest Acidic)	3.8	Chemaxon
pKa (Strongest Basic)	2.64	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	10	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	189.65 Å2	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	200.98 m3·mol-1	Chemaxon
Polarizability	78.72 Å3	Chemaxon
Number of Rings	8	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01b9-0300017900-b1a92eab4059067fbc19
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03dm-0200025900-cb8882e798484ad1edcb
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-014i-0500409200-29ce3b473d055fe6580f
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01ox-4100219600-f02b7823e0f0cea1d0e3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00xr-9700104500-41a5211885facadc4979
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-006w-9500042200-8412e4abeaed255b6c97

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. NS3/4A protein

Kind

Protein

Organism

Hepatitis C Virus

Pharmacological action

Yes

Actions

Inhibitor

General Function

Serine-type peptidase activity

Specific Function

Not Available

Gene Name

NS3/4A

Uniprot ID

B0B3C9

Uniprot Name

Genome polyprotein

Molecular Weight

72789.28 Da

References

1. Lam JT, Salazar L: New combination antiviral for the treatment of hepatitis C. Am J Health Syst Pharm. 2016 Jul 15;73(14):1042-50. doi: 10.2146/ajhp150163. Epub 2016 May 23. [Article]

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Drug created at October 30, 2015 16:02 / Updated at February 21, 2021 18:52