Investigational Drug Details
| Drug ID: | D143 |
| Drug Name: | Ritonavir |
| Synonyms: | |
| Type: | small molecule |
| DrugBank ID: | DB00503 |
| DrugBank Description: | Ritonavir is an HIV protease inhibitor that interferes with the reproductive cycle of HIV. Although it was initially developed as an independent antiviral agent, it has been shown to possess advantageous properties in combination regimens with low-dose ritonavir and other protease inhibitors. It is now more commonly used as a booster of other protease inhibitors and is available in both liquid formulation and as capsules. While ritonavir is not an active antiviral agent against hepatitis C virus (HCV) infection, it is added in combination therapies indicated for treatment of HCV infections as a booster. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of other protease inhibitors such as [DB09297] and overall drug exposure. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) guidelines recommend ritonavir-boosted combination therapies as a first-line therapy for HCV Genotype 1a/b and 4 treatment-naïve patients with or without cirrhosis. Ritonavir is found in a fixed-dose combination product with [DB09296], [DB09183], and [DB09297] 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. Ritonavir is also available as a fixed-dose combination product with [DB09296] and [DB09297] 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, ritonavir is also available as a fixed-dose combination product with [DB09296], [DB09183], and [DB09297] 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. Inclusion of ritonavir can can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with ritonavir-containing combination therapies should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance. |
| PubChem ID: | 392622 |
| CasNo: | 155213-67-5 |
| Repositioning for NAFLD: | Yes |
| SMILES: | CC(C)[C@H](NC(=O)N(C)CC1=CSC(=N1)C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC1=CC=CC=C1)NC(=O)OCC1=CN=CS1)CC1=CC=CC=C1 |
| Structure: |
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| InChiKey: | NCDNCNXCDXHOMX-XGKFQTDJSA-N |
| Molecular Weight: | 720.944 |
| DrugBank Targets: | Human immunodeficiency virus type 1 protease; Nuclear receptor subfamily 1 group I member 2 |
| DrugBank MoA: | Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as *gag* and *pol*. *Gag* encodes proteins involved in the core and the nucleocapsid, while *pol* encodes the the HIV reverse transcriptase, ribonuclease H, integrase, and protease [A19647]. The *pol*-encoded proteins are initially translated in the form of a larger precursoe polypeptide, *gag-pol*, and needs to be cleaved by HIV protease to form other complement proteins [A19647]. Ritonavir prevents the cleavage of the *gag-pol* polyprotein, which results in noninfectious, immature viral particles. Ritonavir is a potent inhibitor of cytochrome P450 CYP3A4 isoenzyme present both in the intestinal tract and liver [A19647]. It is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase [A19648]. Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels [A19647]. |
| DrugBank Pharmacology: | Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Ritonavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Modern protease inhibitors require the use of low-dose ritonavir to boost pharmacokinetic exposure through inhibition of metabolism via the cytochrome P450 3A4 enzyme pathway. |
| DrugBank Indication: | Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. |
| Targets: | |
| Therapeutic Category: | |
| Clinical Trial Progress: | |
| Latest Progress: |
| Trial ID | Source ID | Phases | Status | Study Results | Start Date | Last Update Posted | |
|---|---|---|---|---|---|---|---|
| L1796 | NCT00932048 | WITHDRAWN | NO | 2011-08 | 2013-09-06 | Details | |
| L2281 | NCT01191320 | PHASE2 | COMPLETED | YES | 2010-10 | 2014-07-24 | Details |
| L3091 | NCT01784965 | PHASE3 | COMPLETED | YES | 2009-12 | 2017-04-21 | Details |
| L3689 | NCT03272269 | PHASE1 | COMPLETED | NO | 2017-08-23 | 2019-09-06 | Details |
| L3735 | NCT02697201 | EARLY_PHASE1 | COMPLETED | NO | 2016-07 | 2021-07-27 | Details |
| L4273 | NCT00135096 | PHASE3 | COMPLETED | NO | 2004-08 | 2011-01-11 | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T03 | Angiotensin-converting enzyme | ACE | INHIBITOR | Target is a single protein chain | P12821 | ACE_HUMAN | Details |
| T06 | Sulfonylurea receptor 1 | ABCC8 | Target is a single protein chain | Q09428 | ABCC8_HUMAN | Details | |
| T47 | Sialin | SLC17A5 | Target is a single protein chain | Q9NRA2 | SLC17A5_HUMAN | Details |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs |
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| Article ID | PMID | Source | Title |
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