Aptivus (tipranavir)

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.

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
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• 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
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• 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
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• 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
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• Conduct a human drug-drug interaction study of tipranavir/ritonavir twice daily and atazanavir.
  Final Report Submission: December 31, 2005
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• 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
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• 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
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• 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
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• 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
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• Conduct a human drug-drug interaction study of tipranavir/ritonavir twice daily and methadone.
  Final Report Submission: September 30, 2005
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• Complete ongoing carcinogenicity study in mice and submit final report.
  Protocol Submission: Completed
  Final Report Submission: December 31, 2006
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• Complete ongoing carcinogenicity study in rats and submit final report.
  Protocol Submission: Completed
  Final Report submission: December 31, 2005
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• 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
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• 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
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• Assess metabolic changes being studied in a sub-study of 1182.33.
  Protocol Submission: Completed
  Final Report Submission: September 30, 2006
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• 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
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• 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
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• 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
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• 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
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• Conduct a formal QT prolongation study.
  Protocol Submission: SPA Complete
  Final report Submission: June 30, 2006

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.

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.

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

For additional information regarding Aptivus or HIV-1 infections, please visit the Aptivus web page.