TIPRANAVIR DISODIUM

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C31H31F3N2O5S.2Na
Molecular Weight	646.628
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Na+].[Na+].CCC[C@@]2(CCC1=CC=CC=C1)CC([O-])=C([C@H](CC)C3=CC=CC([N-]S(=O)(=O)C4=NC=C(C=C4)C(F)(F)F)=C3)C(=O)O2

InChI

InChIKey=ZBWMQTUSVWBMQE-KPHXKKTMSA-M

InChI=1S/C31H32F3N2O5S.2Na/c1-3-16-30(17-15-21-9-6-5-7-10-21)19-26(37)28(29(38)41-30)25(4-2)22-11-8-12-24(18-22)36-42(39,40)27-14-13-23(20-35-27)31(32,33)34;;/h5-14,18,20,25H,3-4,15-17,19H2,1-2H3,(H,37,38);;/q-1;2*+1/p-1/t25-,30-;;/m1../s1

HIDE SMILES / InChI

Molecular Formula	Na
Molecular Weight	22.9898
Charge	1
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C31H32F3N2O5S
Molecular Weight	601.656
Charge	-1
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/16802849 | https://www.ncbi.nlm.nih.gov/pubmed/9719600 | http://adisinsight.springer.com/drugs/800008750

Tipranavir (PNU-140690, trade mark APTIVUS) is a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. Tipranavir has potent in vitro activity against a variety of HIV-1 laboratory strains and clinical isolates, including those resistant to ritonavir, as well as HIV-2. The drug is launched in several countries, including the US and in the EU. APTIVUS, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Human immunodeficiency virus type 1 protease 35 Target ID: CHEMBL243 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	Inhibitor 8297		8.0 pM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV-1 infection 151 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	Primary		Approved 8429	APTIVUS Approved Use APTIVUS, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor (PI). This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 48 weeks duration in treatment-experienced adults and one open-label 48-week study in pediatric patients age 2 to 18 years. The adult studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy. The following points should be considered when initiating therapy with APTIVUS/ritonavir: The use of APTIVUS/ritonavir in treatment-naïve patients is not recommended [ see Warnings and Precautions (5.1) Launch Date 2005

C_max

Value	Dose	Co-administered	Analyte	Population
77.6 μM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FED
94.8 μM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FED
135 μM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	375 mg/m² 2 times / day steady-state, oral dose: 375 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
710 μM × h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FED
851 μM × h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FED
1190 μM × h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	375 mg/m² 2 times / day steady-state, oral dose: 375 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FED
5.5 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FED
8.1 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	375 mg/m² 2 times / day steady-state, oral dose: 375 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered: Ritonavir	Ritonavir	TIPRANAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FED

Doses

Dose	Population	Adverse events
500 mg 2 times / day multiple, oral Recommended Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Co-administed with:: ritonavir, oral(200 mg, b.i.d.) Sources: https://pubmed.ncbi.nlm.nih.gov/26730818 Page: p.11	unhealthy, 18–65 n = 186 Health Status: unhealthy Condition: HIV-1 infection Age Group: 18–65 Sex: M+F Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/26730818 Page: p.11	Disc. AE: Gastrointestinal disorder NOS, Gastrointestinal disorder NOS... AEs leading to discontinuation/dose reduction: Gastrointestinal disorder NOS (grade 1, 1%) Gastrointestinal disorder NOS (moderate, 2.1%) Gastrointestinal disorder NOS (severe, 1%) Transaminases increased (grade 1, 1%) Transaminases increased (moderate, 1.6%) Transaminases increased (severe, 4.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/26730818 Page: p.11
1200 mg 2 times / day multiple, oral Highest studied dose Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15097154 Page: p.381	unhealthy, 35.2 n = 10 Health Status: unhealthy Condition: HIV-1 infection Age Group: 35.2 Sex: M+F Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/15097154 Page: p.381	Sources: https://pubmed.ncbi.nlm.nih.gov/15097154 Page: p.381
500 mg 2 times / day multiple, oral Recommended Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Co-administed with:: ritonavir, oral(200 mg, b.i.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf Page: p.1	Disc. AE: Hepatitis, Hepatic decompensation... AEs leading to discontinuation/dose reduction: Hepatitis Hepatic decompensation Intracranial hemorrhage Platelet aggregation Coagulation abnormal Diabetes mellitus Hyperglycemia Immune reconstitution syndrome Fat redistribution Lipids increased Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf Page: p.1
500 mg 2 times / day multiple, oral Recommended Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Co-administed with:: ritonavir, oral(200 mg, b.i.d.) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf Page: p.1, 5	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf Page: p.1, 5	Disc. AE: Rash... AEs leading to discontinuation/dose reduction: Rash (0.5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021814s011lbl.pdf Page: p.1, 5

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 substrate 1737 inducer 781	inducer 389 inhibitor 1767	inhibitor 1852 substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 214 P-gp 1461 CYP1A2 1524 CYP2C19 1478 OATP2B1 123 UGT enzymes 4 Ca2+ channels 57	P-gp 1537	P-gp 257 CYP1A2 701 UGT enzymes 2 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 7.0	inconclusive
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 7.0	inconclusive
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 7.0	inconclusive
Ca2+ channels 60	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 13.0	inconclusive
UGT enzymes 4	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 7.0	inconclusive
UGT enzymes 4	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 7.0	inconclusive
P-gp 1650	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 34, 109, 127	likely
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0	moderate [IC50 16.3 uM]	yes (co-administration study) Comment: coadministration with dextromethorphan led to potent inhibition of CYP2D5 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 22, 102	moderate
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 34.0	weak
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0	yes [IC50 0.26 uM]	no (co-administration study) Comment: coadministration with warfarin had no effect Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0	yes [IC50 2.3 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0	yes [IC50 2.7 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0	yes [IC50 >50 uM]	yes (co-administration study) Comment: coadministration with caffeine led to moderate induction at steady state Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 100.0
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 34.0	yes
OATP2B1 126	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/20507927/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 96.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr1.pdf Page: 2, 7, 34	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 96.0	yes	yes (co-administration study) Comment: coadministration with ketaconazole inhibited the metabolism of tipranavir by 90% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_biopharmr2.pdf Page: 96.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21814_000_Aptivus_pharmr1.pdf Page: 4, 10, 16, 17

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63628	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63628
ChemicalBook	CB9501005	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9501005
MolPort	MolPort-003-850-561	https://www.molport.com/shop/molecule-link/MolPort-003-850-561
ZINC	ZINC000100016058	http://zinc15.docking.org/substances/ZINC000100016058
eMolecules	36754763	https://www.emolecules.com/cgi-bin/more?vid=36754763

PubMed

Title	Date	PubMed
Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples.	2000 Sep 8	10997398
Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir.	2005 Oct	16122817
Tipranavir: PNU 140690, tipranivir.	2006	16620137
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization.	2007 Sep 28	17635930
Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA's Adverse Event Reporting System.	2008 Nov	19025478
In vitro activity of antiretroviral drugs against Plasmodium falciparum.	2011 Nov	21876053
Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11).	2013 Dec	24014644

Patents

Sample Use Guides

In Vivo Use Guide

Adults: 500 mg APTIVUS® (tipranavir), co-administered with 200 mg ritonavir, twice daily. Pediatric patients (age 2 to 18 years): Dosing is based on body weight or body surface area not to exceed adult dose.

Route of Administration: Oral

In Vitro Use Guide

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with EC50 ranging from 0.03 to 0.07 µM (18-42 ng/mL)

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:55:09 GMT 2023` Edited by `admin` on `Fri Dec 15 15:55:09 GMT 2023`
Record UNII	9BAN2XG1ZW
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TIPRANAVIR DISODIUM

Official Name

English

TIPRANAVIR SODIUM [MART.]

Common Name

English

TIPRANAVIR SODIUM

Common Name

English

TIPRANAVIR DISODIUM [USAN]

Common Name

English

Tipranavir Sodium [WHO-DD]

Common Name

English

PNU-140690E

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C97366