RITONAVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C37H48N6O5S2
Molecular Weight	720.944
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

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](CC2=CC=CC=C2)NC(=O)OCC3=CN=CS3)CC4=CC=CC=C4

InChI

InChIKey=NCDNCNXCDXHOMX-XGKFQTDJSA-N

InChI=1S/C37H48N6O5S2/c1-24(2)33(42-36(46)43(5)20-29-22-49-35(40-29)25(3)4)34(45)39-28(16-26-12-8-6-9-13-26)18-32(44)31(17-27-14-10-7-11-15-27)41-37(47)48-21-30-19-38-23-50-30/h6-15,19,22-25,28,31-33,44H,16-18,20-21H2,1-5H3,(H,39,45)(H,41,47)(H,42,46)/t28-,31-,32-,33-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C37H48N6O5S2
Molecular Weight	720.944
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020659s065,022417s017lbl.pdf
Curator's Comment: description was created based on several sources, including: http://www.rxlist.com/norvir-drug.htm https://www.drugs.com/mtm/ritonavir.html http://www.wikidoc.org/index.php/Ritonavir

Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Ritonavir binds to the protease active site and inhibits the activity of the enzyme. It is FDA approved for the treatment of HIV-1 infection. In patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving Ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. The most frequently reported adverse drug reactions among patients receiving Ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Cytochrome P450 2B6 19 Target ID: CHEMBL4729 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11159797	Inhibitor 8297	2.2 µM [IC50]
Cytochrome P450 3A 22 Target ID: CHEMBL2364675 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10952482	Inhibitor 8297	0.14 µM [IC50]
Human immunodeficiency virus type 1 protease 35 Target ID: CHEMBL243 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17627597	Inhibitor 8297	0.01 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV-1 infection 151 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020659s065,022417s017lbl.pdf	Primary		Approved 8429	NORVIR Approved Use KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The following points should be considered when initiating therapy with KALETRA: The use of other active agents with KALETRA is associated with a greater likelihood of treatment response [see Clinical Pharmacology (12.4) and Clinical Studies (14) Launch Date 1996

C_max

Value	Dose	Co-administered	Analyte	Population
11.2 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020659Orig1s000rev.pdf	600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		RITONAVIR unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
129 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020659Orig1s000rev.pdf	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:		RITONAVIR unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
5 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020659Orig1s000rev.pdf	600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		RITONAVIR unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
2% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020659Orig1s000rev.pdf	600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		RITONAVIR unknown	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg 1 times / day steady, oral Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: steady Dose: 200 mg, 1 times / day Co-administed with:: elvitegravir(125 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	healthy, 29 years n = 10 Health Status: healthy Age Group: 29 years Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	Disc. AE: Death fetal... AEs leading to discontinuation/dose reduction: Death fetal (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/
50 mg 1 times / day steady, oral Studied dose Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Co-administed with:: elvitegravir(125 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	healthy, 29 years n = 10 Health Status: healthy Age Group: 29 years Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	Disc. AE: Hypertension... AEs leading to discontinuation/dose reduction: Hypertension (grade 2, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/
600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	unhealthy, adult Health Status: unhealthy Condition: HIV-1 Age Group: adult Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	Other AEs: Gastrointestinal disorder NOS, Lipids abnormal... Other AEs: Gastrointestinal disorder NOS Lipids abnormal Insulin resistance Lipoatrophy Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/

AEs

AE	Significance	Dose	Population
Death fetal	1 patient Disc. AE	200 mg 1 times / day steady, oral Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: steady Dose: 200 mg, 1 times / day Co-administed with:: elvitegravir(125 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	healthy, 29 years n = 10 Health Status: healthy Age Group: 29 years Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/
Hypertension	grade 2, 1 patient Disc. AE	50 mg 1 times / day steady, oral Studied dose Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Co-administed with:: elvitegravir(125 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	healthy, 29 years n = 10 Health Status: healthy Age Group: 29 years Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/
Gastrointestinal disorder NOS		600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	unhealthy, adult Health Status: unhealthy Condition: HIV-1 Age Group: adult Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/
Insulin resistance		600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	unhealthy, adult Health Status: unhealthy Condition: HIV-1 Age Group: adult Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/
Lipids abnormal		600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	unhealthy, adult Health Status: unhealthy Condition: HIV-1 Age Group: adult Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/
Lipoatrophy		600 mg 2 times / day steady, oral Recommended Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/	unhealthy, adult Health Status: unhealthy Condition: HIV-1 Age Group: adult Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/18815591/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inducer 389 inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 214 P-gp 1461 CYP2C19 1478 CYP2E1 882 CYP1A2 1524	CYP3A 191 CYP2D 1 CYP3A5 395	CYP3A 129 CYP1A2 701 CYP2C19 293 CYP2B6 547 UGT 29 P-gp 257

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9549640/ Page: -	no
CYP2E1 970	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9549640/ Page: -	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 \| https://pubmed.ncbi.nlm.nih.gov/9549640/ Page: 2.0	yes [IC50 17.3 uM]	yes (co-administration study) Comment: A published trial (Aarnoutse et al 2005) cited previously published data that reported a 145% increase in desipramine with ritonavir 500 mg twice daily dosing. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 \| https://pubmed.ncbi.nlm.nih.gov/9549640/ Page: 2.0
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9549640/ Page: -	yes [IC50 23.5 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9549640/ Page: -	yes [IC50 6.2 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 Page: 2.0	yes
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ClinPharmR.pdf#page=19 Page: 19.0	yes
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ClinPharmR.pdf#page=19 Page: 19.0	yes
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 Page: 2.0	yes
CYP3A 298	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 Page: 2.0	yes
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 Page: 2.0	yes
P-gp 1650	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ClinPharmR.pdf#page=51 Page: 51.0	yes
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ClinPharmR.pdf#page=51 Page: 51.0	yes
UGT 59	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ClinPharmR.pdf#page=19 Page: 19.0	yes

Drug as victim

Target	Modality	Activity
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 Page: 2.0	major
CYP3A4 1737	substrate 3367 Sources: https://dmd.aspetjournals.org/content/26/6/552 Page: -	yes [Km 0.05 uM]
CYP3A5 395	substrate 3367 Sources: https://dmd.aspetjournals.org/content/26/6/552 Page: -	yes [Km 0.21 uM]
CYP2D 1	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/020659s013_Norvir_biopharmr.PDF#page=2 Page: 2.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.sciencedirect.com/science/article/pii/S0140673605179501 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45409	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45409
ChemicalBook	CB0119429	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB0119429
MolPort	MolPort-000-883-877	https://www.molport.com/shop/molecule-link/MolPort-000-883-877
Selleck Chemicals	Ritonavir	http://www.selleckchem.com/products/Ritonavir.html
ZINC	ZINC000003944422	http://zinc15.docking.org/substances/ZINC000003944422
eMolecules	877483	https://www.emolecules.com/cgi-bin/more?vid=877483

PubMed

Title	Date	PubMed
Protease inhibitors shine in triple combinations.	1996 Mar	11363243
Resolution of chronic hepatitis B after ritonavir treatment in an HIV-infected patient.	1999 Jun 3	10357637
HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells.	1999 Sep-Oct	10551732
Structural and kinetic analyses of the protease from an amprenavir-resistant human immunodeficiency virus type 1 mutant rendered resistant to saquinavir and resensitized to amprenavir.	2000 Aug	10906218
BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents.	2000 Aug	10898681
Inhibitory effect of human immunodeficiency virus protease inhibitors on multidrug resistance transporter P-glycoproteins.	2000 Dec	11145192
Increasing cerebrospinal fluid chemokine concentrations despite undetectable cerebrospinal fluid HIV RNA in HIV-1-infected patients receiving antiretroviral therapy.	2000 Dec 15	11141242
Potential interaction between ritonavir and carbamazepine.	2000 Jul	10907977
In vitro activity of human immunodeficiency virus protease inhibitors against Pneumocystis carinii.	2000 May	10823762
Anti-toxoplasma activities of antiretroviral drugs and interactions with pyrimethamine and sulfadiazine in vitro.	2000 Sep	10952623
Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.	2000 Sep 7	10978186
An open-label randomized trial to evaluate different therapeutic strategies of combination therapy in HIV-1 infection: design, rationale, and methods of the initio trial.	2001 Apr	11306154
Anti-human immunodeficiency virus activity of YK-FH312 (a betulinic acid derivative), a novel compound blocking viral maturation.	2001 Apr	11257038
Persistent dyslipidemia in HIV-infected individuals switched from a protease inhibitor-containing to an efavirenz-containing regimen.	2001 Apr 1	11317084
Determination of serum levels of thirteen human immunodeficiency virus-suppressing drugs by high-performance liquid chromatography.	2001 Apr 13	11355843
Determination of interaction kinetic constants for HIV-1 protease inhibitors using optical biosensor technology.	2001 Apr 15	11401294
A pilot study of the use of mycophenolate mofetil as a component of therapy for multidrug-resistant HIV-1 infection.	2001 Apr 15	11391161
[An option even for patients with multiple pretreatment].	2001 Apr 2	11373796
[Overcoming weaknesses in therapy. Protease inhibitors with high IQ].	2001 Apr 2	11373795
[Improving the pharmacokinetics of protease inhibitors in a more innovative manner. HIV drugs administered in a more clever way].	2001 Apr 2	11373769
[Indinavir-ritonavir combination: pharmacologic results and tolerance in patients infected by HIV].	2001 Apr 21	11360738
Antiviral drugs: current state of the art.	2001 Aug	11418355
[Long-term immunologic response in HIV-infected patients with CD4 cell counts	2001 Feb	11240420
Human immunodeficiency virus (HIV) protease inhibitors have no effect on hepatitis C virus (HCV) serum levels of HIV-HCV co-infected patients.	2001 Feb	11165122
CYP3A4 is the major CYP isoform mediating the in vitro hydroxylation and demethylation of flunitrazepam.	2001 Feb	11159802
Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion.	2001 Feb	11159797
Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression.	2001 Feb 15	11170979
Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission.	2001 Jan 1	11176268
ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results.	2001 Jan 5	11192874
Lopinavir/ritonavir: a protease inhibitor combination.	2001 Jan 8	11151088
New developments in anti-HIV chemotherapy.	2001 Jan-Feb	11347962
Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers.	2001 Jun	11422019
Simultaneous determination of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma by reversed-phase high-performance liquid chromatography.	2001 Jun 15	11417878
Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377).	2001 Jun 15	11372025
ABT 378/r: a novel inhibitor of HIV-1 protease in haemodialysis.	2001 Mar 30	11317012
Structure-activity studies of FIV and HIV protease inhibitors containing allophenylnorstatine.	2001 May	11377177
A potential role for interleukin-7 in T-cell homeostasis.	2001 May 15	11342421
Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment.	2001 May 25	11399984
Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection.	2001 May 4	11399957

Patents

Sample Use Guides

In Vivo Use Guide

600 mg twice-day with meals. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily.

Route of Administration: Oral

In Vitro Use Guide

Ritonavir diminished the growth rate of Candida albicans as well as the activity of its secreted aspartyl proteinases (Saps) in a nitrogen-limited medium, yeast carbon base and bovine serum albumin (YCB-BSA). This inhibition occurred in a dose-dependent fashion; with 8 mg/l of ritonavir a partial growth inhibition (44%) was produced.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:29:49 GMT 2023` Edited by `admin` on `Fri Dec 15 15:29:49 GMT 2023`
Record UNII	O3J8G9O825
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

RITONAVIR

Official Name

English

NORVIR

Brand Name

English

RITONAVIR [VANDF]

Common Name

English

RITONAVIR [MI]

Common Name

English

VIRITON

Brand Name

English

EMPETUS

Brand Name

English

PAXLOVID COMPONENT RITONAVIR

Brand Name

English

ritonavir [INN]

Common Name

English

ABBOTT-84538

Code

English

VIEKIRAX COMPONENT RITONAVIR

Brand Name

English

RITOVIR

Brand Name

English

KALETRA COMPONENT RITONAVIR

Common Name

English

RITONAVIR [HSDB]

Common Name

English

RITONAVIR [USP-RS]

Common Name

English

NSC-693184

Code

English

ABT-538

Code

English

RITONAVIR COMPONENT OF PAXLOVID

Brand Name

English

RITONAVIR COMPONENT OF VIEKIRAX

Brand Name

English

RTV

Common Name

English

RITONAVIR [EMA EPAR]

Common Name

English

RITONAVIR [JAN]

Common Name

English

Ritonavir [WHO-DD]

Common Name

English

RITONAVIR COMPONENT OF KALETRA

Common Name

English

RITONAVIR [ORANGE BOOK]

Common Name

English

RITONAVIRUM [WHO-IP LATIN]

Common Name

English

A-84538

Code

English

RITOMUNE

Brand Name

English

RITONAVIR RELATED COMPOUNDS MIXTURE

Common Name

English

2,7,10,12-TETRAAZATRIDECANOIC ACID, 4-HYDROXY-12-METHYL-9-(1-METHYLETHYL)-13-(2-(1-METHYLETHYL)-4-THIAZOLYL)-8,11-DIOXO-3,6-BIS(PHENYLMETHYL)-, 5-THIAZOLYLMETHYL ESTER, (3S,4S,6S,9S)-

Systematic Name

English

RITONAVIR [MART.]

Common Name

English

2,4,7,12-TETRAAZATRIDECAN-13-OIC ACID, 10-HYDROXY-2-METHYL-5-(1-METHYLETHYL)-1-(2-(1-METHYLETHYL)-4-THIAZOLYL)-3,6-DIOXO-8,11-BIS(PHENYLMETHYL)-5-THIAZOLYLMETHYL ESTER (5S-(5R*,8R*,10R*,11R*))-

Common Name

English

RITONAVIR [USP IMPURITY]

Common Name

English

RITONAVIR [USP MONOGRAPH]

Common Name

English

RITONAVIR RELATED COMPOUNDS MIXTURE [USP-RS]

Common Name

English

RITONAVIR [WHO-IP]

Common Name

English

VIEKIRAX

Brand Name

English

5-Thiazolylmethyl [(αS)-α-[(1S,3S)-1-hydroxy-3-[(2S)-2-[3-[(2-isopropyl-4-thiazolyl)methyl]-3-methylureido]-3-methylbutyramido]-4-phenylbutyl]phenethyl]carbamate

Common Name

English

RITONAVIR [USAN]

Common Name

English

Classification Tree Code System Code

LIVERTOX

NBK548747