Aptivus (tipranavir)
The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
General Information
Aptivus (tipranavir), is a non-peptide protease inhibitor. The
drug disrupts the formation of mature viral particles by disrupting
synthesis of viral proteins.
Aptivus is specifically indicated as a combination therapy with
the approved drug ritonavir, for the treatment of HIV-1-infected
adult patients with evidence of viral replication. It is indicated
as a second line or later therapy, for use inpatients who are
highly treatment experienced or whose HIV-1 strain has shown
resistance to other protease inhibitors.
Aptivus is supplied as an oblong pink gelatin capsule. The
recommended dose is 250 mg twice daily in combination with 200 mg
ritonavir twice daily. The drug should be administered in
combination with food.
Clinical Results
FDA Approval
Approval of Aptivus was based on 2 ongoing, randomized, controlled,
open-label, multicenter phase III clinical trials (RESIST-1 and
RESIST-2), which enrolled a combined 1159 triple antiretroviral
class experienced patients with experience with at least two prior
protease-inhibitor-based antiretroviral regimens, including one
failure, and at least one, but not more than two, primary protease
gene mutations. Subjects were randomized to receive either Aptivus
in combination with 200 mg ritonavir plus an optimum background
regimen (OBR), or a control regimen of an approved protease
inhibitor (lopinavir, amprenavir, saquinavir or indinavir) in
combination with ritonavir plus OBR for 24 weeks. Trial data
indicated that Aptivus produced more virological responders than
approved protease inhibitors, with 40% of subjects achieving a
reduction of HIV-1 RNA of at least 1 log10, vs. 18% for control.
Furthermore, fewer individuals on Aptivus experienced virologic
failure than approved drugs, with 35% failing to achieve at least a
0.5 log10 drop from baseline and a viral RNA load <100,000
copies by week 8, 12% achieving initial response but rebounding by
week 24, and 7% never responding, compared to 59%, 11% and 8% for
the control group, respectively. These results indicate that
Aptivus may provide superior efficacy compared to other protease
inhibitors in second-line-or-later regimens of antiretroviral
therapy for HIV-1 infections.
Ongoing Study Commitments
- Submit the study reports for the 48 week data of the ongoing
Phase 3 study RESIST-1 (study protocol 1182.12).
Report Submission due: September 30, 2006
- Submit the study reports for the 48 week data of the ongoing
Phase 3 study RESIST-2 (study protocol 1182.48).
Report Submission due: September 30, 2006
- Assess pharmacokinetics, safety and antiviral activity in two
alternative doses of either tipranavir/ritonavir liquid formulation
or capsules in addition to safety, in antiretroviral naive and
experienced children and adolescents between 2 and 18 years of
age.
Protocol Submission: Completed
Final Report Submission: June 30, 2006
- Evaluate dose requirements and safety in pediatric patients age
2 weeks to 2 years with HIV-1 infection after review of 48 week
data from the 2 to 18 year old children in trial 1182.14 with the
Division of Antiviral Drug Products (DAVDP).
Protocol Submission: September 30, 2006
Final Report Submission: January 31, 2009
- Conduct a human drug-drug interaction study of
tipranavir/ritonavir twice daily and atazanavir.
Final Report Submission: December 31, 2005
- Conduct a human drug-drug interaction study of
tipranavir/ritonavir twice daily and buprenorphine/naloxone.
Protocol Submission: July 15, 2005
Final Report Submission: June 30, 2006
- Conduct a human drug-drug interaction study of
tipranavir/ritonavir twice daily and carbamazepine.
Protocol Submission: July 15, 2005
Final Report Submission: September 30, 2006
- Conduct a human drug-drug interaction study of
tipranavir/ritonavir twice daily and tadalafil.
Protocol Submission: August 31, 2005
Final Report Submission: December 31, 2006
- Conduct a human drug-drug interaction study of
tipranavir/ritonavir twice daily and ribavirin/pegylated IFN alpha
2a.
Protocol Submission: August 31, 2005
Final Report Submission: June 30, 2007
- Conduct a human drug-drug interaction study of
tipranavir/ritonavir twice daily and methadone.
Final Report Submission: September 30, 2005
- Complete ongoing carcinogenicity study in mice and submit final
report.
Protocol Submission: Completed
Final Report Submission: December 31, 2006
- Complete ongoing carcinogenicity study in rats and submit final
report.
Protocol Submission: Completed
Final Report submission: December 31, 2005
- Assess the long term (48 week) antiviral efficacy and safety of
tipranavir/ritonavir in ARV treatment naive patients through the
conduct of study 1182.33.
Protocol Submission: Completed
Final Report Submission: September 30, 2006
- Evaluate drug resistance in viruses from patients with
virologic rebound on initial ART (in 1182.33).
Protocol Submission: Completed
Final Report Submission: September 30, 2006
- Assess metabolic changes being studied in a sub-study of
1182.33.
Protocol Submission: Completed
Final Report Submission: September 30, 2006
- Conduct a 48-week prospective observational diversity cohort
study with tipranavir/ritonavir twice daily stratified by race and
gender in HIV-positive patients to assess efficacy and safety,
including potential risk parameters such as CD4+ cell count.
Protocol Submission: March 30, 2006 Final Report Submission:
September 1, 2008
- Conduct a 48-week prospective observational cohort study with
tipranavir/ritonavir twice daily in patients co-infected with HIV
and HBV or HCV to assess efficacy and safety. BI will discuss
potential therapeutic drug monitoring substudy for this protocol
with the FDA.
Protocol Submission: March 30, 2006
Final Report Submission: July 1, 2008
- Assess tipranavir/ritonavir pharmacokinetics in HIV-negative
subjects with Child-Pugh B liver disease.
Protocol Submission: December 31, 2006
Final Report Submission: December 31, 2007
- Conduct a CYP/P-gp mechanistic study to determine effect of
tipranavir/ritonavir on individual CYPs.
Protocol Submission: September 30, 2005
Final Report Submission: December 31, 2006
- Conduct a formal QT prolongation study.
Protocol Submission: SPA Complete
Final report Submission: June 30, 2006
Side Effects
Adverse events associated with the use of Aptivus may include,
but are not limited to, the following:
- Anemia/Neutropenia
- Pancreatitis
- Pyrexia
- Hepatic Failure
- Anorexia
- Peripheral Neuropathy
- Lipoatrophy
- Diarrhea
- Nausea
- Fatigue
- Headache
In addition, considerable pharmacokinetic interaction has been
noted between Aptivus and a number of other classes of drugs, with
significant effect on peak and trough plasma drug concentrations,
and on total drug exposure. Some of these interactions can be
serious or life-threatening. Patients should discuss potential
interactions with their physicians.
Mechanism of Action
Aptivus is a member of the 4-hydroxy-5,6-dihydro-2-pyrone
sulfonamide class, with activity as a non-peptide protease
inhibitor. The drug has been shown to selectively inhibit
virus-specific processing of viral Gag and Gag-pol polyproteins,
preventing formation of funtional mature virions.
Literature References
Kandula VR, Khanlou H, Farthing C. Tipranavir:
a novel second-generation nonpeptidic protease inhibitor.
Expert Review of Anti-Infective Therapy 2005
Feb;3(1):9-21
Cheonis N. Tipranavir: the first nonpeptidic
protease inhibitor. Bulletin of Experimental Treatments for
AIDS 2004 Winter;16(2):15-7
Bulgheroni E, Citterio P, Croce F, Lo Cicero M, Vigano
O, Soster F, Chou TC, Galli M, Rusconi S. Analysis of
protease inhibitor combinations in vitro: activity of lopinavir,
amprenavir and tipranavir against HIV type 1 wild-type and
drug-resistant isolates. Journal of Antimicrobial
Chemotherapy 2004 Mar;53(3):464-8
Larder BA, Hertogs K, Bloor S, van den Eynde CH, DeCian
W, Wang Y, Freimuth WW, Tarpley G. Tipranavir inhibits
broadly protease inhibitor-resistant HIV-1 clinical samples.
AIDS 2000 Sep 8;14(13):1943-8
Additional Information
For additional information regarding Aptivus or HIV-1
infections, please visit the Aptivus web page.