U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

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 of TIPRANAVIR DISODIUM

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
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

Curator's Comment: Tipranavir do not reach therapeutical concentrations in CSF

Originator

Curator's Comment: # Pharmacia & Upjohn (now Pfizer)

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
8.0 pM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
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

1.1193984E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
77.6 μM
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: FED
94.8 μM
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: FED
135 μM
375 mg/m² 2 times / day steady-state, oral
dose: 375 mg/m²
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: CHILD
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
710 μM × h
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: FED
851 μM × h
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: FED
1190 μM × h
375 mg/m² 2 times / day steady-state, oral
dose: 375 mg/m²
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: CHILD
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
6 h
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: MALE
food status: FED
5.5 h
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: FED
8.1 h
375 mg/m² 2 times / day steady-state, oral
dose: 375 mg/m²
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: CHILD
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
0.1%
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: Ritonavir
TIPRANAVIR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: FED
Doses

Doses

DosePopulationAdverse 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: 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: 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: 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: 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: 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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: 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: 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: Page: p.1, 5
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1, 5
Disc. AE: Rash...
AEs leading to
discontinuation/dose reduction:
Rash (0.5%)
Sources: Page: p.1, 5
AEs

AEs

AESignificanceDosePopulation
Gastrointestinal disorder NOS grade 1, 1%
Disc. AE
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: 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: Page: p.11
Transaminases increased grade 1, 1%
Disc. AE
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: 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: Page: p.11
Transaminases increased moderate, 1.6%
Disc. AE
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: 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: Page: p.11
Gastrointestinal disorder NOS moderate, 2.1%
Disc. AE
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: 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: Page: p.11
Gastrointestinal disorder NOS severe, 1%
Disc. AE
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: 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: Page: p.11
Transaminases increased severe, 4.8%
Disc. AE
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: 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: Page: p.11
Coagulation abnormal Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Diabetes mellitus Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Fat redistribution Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Hepatic decompensation Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Hepatitis Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Hyperglycemia Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Immune reconstitution syndrome Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Intracranial hemorrhage Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Lipids increased Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Platelet aggregation Disc. AE
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: Page: p.1
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1
Rash 0.5%
Disc. AE
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: Page: p.1, 5
unhealthy
Health Status: unhealthy
Condition: HIV-1 infection
Sources: Page: p.1, 5
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
inconclusive
inconclusive
inconclusive
inconclusive
inconclusive
inconclusive
likely
moderate [IC50 16.3 uM]
yes (co-administration study)
Comment: coadministration with dextromethorphan led to potent inhibition of CYP2D5
Page: 100.0
moderate
weak
yes [IC50 0.26 uM]
no (co-administration study)
Comment: coadministration with warfarin had no effect
Page: 100.0
yes [IC50 2.3 uM]
yes [IC50 2.7 uM]
yes [IC50 >50 uM]
yes (co-administration study)
Comment: coadministration with caffeine led to moderate induction at steady state
Page: 100.0
yes
yes
Drug as victim

Drug as victim

Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Structure-based design of HIV protease inhibitors: sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones as non-peptidic inhibitors.
1996 Oct 25
Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor.
1997 May
In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates.
1997 Nov
Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class.
1998 Aug 27
In-vitro tipranavir susceptibility of HIV-1 isolates with reduced susceptibility to other protease inhibitors.
2000 Jan 7
Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples.
2000 Sep 8
Design of HIV-1 protease inhibitors active on multidrug-resistant virus.
2005 Mar 24
Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir.
2005 Oct
Tipranavir: PNU 140690, tipranivir.
2006
Susceptibility to protease inhibitors in HIV-2 primary isolates from patients failing antiretroviral therapy.
2006 Apr
Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance.
2007 Nov
Characterization of a novel human immunodeficiency virus type 1 protease inhibitor, A-790742.
2008 Apr
Hepatic profile analyses of tipranavir in Phase II and III clinical trials.
2009 Dec 14
Cytotoxicological analysis of a gp120 binding aptamer with cross-clade human immunodeficiency virus type 1 entry inhibition properties: comparison to conventional antiretrovirals.
2009 Jul
Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
2010 Aug
Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance.
2010 May
In vitro activity of antiretroviral drugs against Plasmodium falciparum.
2011 Nov
Activity of human immunodeficiency virus type 1 protease inhibitors against the initial autocleavage in Gag-Pol polyprotein processing.
2012 Jul
Novel method to assess antiretroviral target trough concentrations using in vitro susceptibility data.
2012 Nov
Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11).
2013 Dec
GRL-0519, a novel oxatricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor (PI), potently suppresses replication of a wide spectrum of multi-PI-resistant HIV-1 variants in vitro.
2013 May
P2' benzene carboxylic acid moiety is associated with decrease in cellular uptake: evaluation of novel nonpeptidic HIV-1 protease inhibitors containing P2 bis-tetrahydrofuran moiety.
2013 Oct
Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance.
2013 Sep 19
Patents

Sample Use Guides

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
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 UTC 2023
Edited
by admin
on Fri Dec 15 15:55:09 UTC 2023
Record UNII
9BAN2XG1ZW
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TIPRANAVIR DISODIUM
USAN  
USAN  
Official Name English
TIPRANAVIR SODIUM [MART.]
Common Name English
TIPRANAVIR SODIUM
MART.   WHO-DD  
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
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
Code System Code Type Description
USAN
JJ-76
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
EPA CompTox
DTXSID80940718
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
PUBCHEM
163296
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
CAS
191150-83-1
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
FDA UNII
9BAN2XG1ZW
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
NCI_THESAURUS
C66604
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
DRUG BANK
DBSALT001882
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
ChEMBL
CHEMBL222559
Created by admin on Fri Dec 15 15:55:09 UTC 2023 , Edited by admin on Fri Dec 15 15:55:09 UTC 2023
PRIMARY
Related Record Type Details
PARENT -> SALT/SOLVATE
Related Record Type Details
ACTIVE MOIETY