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Tipranavir

A Ritonavir-Boosted Protease Inhibitor

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Abstract

▴ Tipranavir is a non-peptidic HIV-1 protease inhibitor. It binds strongly and selectively, has a favourable resistance profile, and is administered orally twice daily with a subtherapeutic dosage of ritonavir in a ‘boosted’ regimen (TPV/r) in order to increase its bioavailability.

▴ Analysis of clinical isolates from treatment-experienced patients identified the following tipranavir resistance-associated HIV protease mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V.

▴ In two large, well designed phase III trials in protease inhibitor-experienced, HIV-infected patients, the RESIST (Randomised Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir)-1 and -2 studies, oral TPV/r 500mg/200mg twice daily achieved a significantly better virological response after 24 weeks than standard ritonavir-boosted protease inhibitors. This held true for the proportion of patients achieving a ≥1 log 10 decrease in plasma HIV-RNA levels (viral load) [42% and 41% vs 22% and 15%; both p < 0.0001; primary endpoint] and other virological parameters (the proportion of patients with undetectable viral load and total viral load reduction).

▴ In addition, a significantly larger increase in CD4+ cell count was achieved with TPV/r than comparator regimens in these trials.

▴ The most common adverse events in clinical trials of tipranavir were gastrointestinal. The incidence of treatment discontinuation because of adverse events in the RESIST trials was 8% (pooled data).

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2005 Apr 7 [online]. Available from URL: http://AIDSinfo.nih.gov [Accessed 2005 May 10]

  2. Hirsch MS, Brun-Vezinet F, Clotet B, et al. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA panel. Clin Infect Dis 2003; 37: 113–28

    Article  PubMed  Google Scholar 

  3. Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother 2004; 53(1): 4–9

    Article  PubMed  CAS  Google Scholar 

  4. Plosker GL, Figgitt DP. Tipranavir. Drugs 2003; 63(15): 1611–8

    Article  PubMed  CAS  Google Scholar 

  5. Poppe SM, Slade DE, Chong KT, et al. Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor. Antimicrob Agents Chemother 1997 May; 41(5): 1058–63

    PubMed  CAS  Google Scholar 

  6. Larder BA, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 2000 Sep 8; 14(13): 1943–8

    Article  PubMed  CAS  Google Scholar 

  7. Rusconi S, La Seta Catamancio S, Citterio P, et al. Susceptibility to PNU-140690 (tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob Agents Chemother 2000 May; 44(5): 1328–32

    Article  PubMed  CAS  Google Scholar 

  8. Yeni P, MacGregor T, Gathe J, et al. Correlation of viral load reduction and plasma levels in multiple protease inhibitor (PI)-experienced patients taking tipranavir/ritonavir in a phase IIB trial: BI 1182.52 [abstract no. 528 plus poster]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston (MA)

  9. Muzammil S, Kang LW, Armstrong AA, et al. Unique response of tipranavir to multi-drug resistant HIV-1 proteases suggests new ways of combating drug resistance [abstract no. 63]. Antiviral Ther 2005; 10 Suppl. 1: S70

    Google Scholar 

  10. Chong KT, Pagano PJ. In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates. Antimicrob Agents Chemother 1997 Nov; 41(11): 2367–73

    PubMed  CAS  Google Scholar 

  11. Bulgheroni E, Citterio P, Croce F, et al. Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against HIV type 1 wild-type and drug-resistant isolates. J Antimicrob Chemother 2004 Mar; 53(3): 464–8

    Article  PubMed  CAS  Google Scholar 

  12. Molla A, Mo H, Vasavanonda S, et al. In vitro antiviral interaction of lopinavir with other protease inhibitors. Antimicrob Agents Chemother 2002 Jul; 46(7): 2249–53

    Article  PubMed  CAS  Google Scholar 

  13. Doyon L, Tremblay S, Wardrop E, et al. Characterization of HIV-1 isolates showing decreased susceptibility to tipranavir and their inhibition by tipranavir containing drug mixtures [abstract plus poster]. XII International HIV Drug Resistance Workshop; 2003 Jun 10–14; Los Cabos, Mexico

  14. Aptivus® (tipranavir) capsules, 250mg: prescribing information. Ridgefield (CT): Boehringer Ingelheim, 2005 Jun 23

  15. McCallister S, Kohlbrenner V, Squires K, et al. Characterization of the impact of genotype, phenotype, and inhibitory quotient on antiviral activity of tipranavir in highly treatment-experienced patients [abstract no. 12]. Antiviral Ther 2003 Jun; 8 (3): S15-6. Plus poster presented at the XII International HIV Drug Resistance Workshop; 2003 Jun 10–14; Los Cabos, Mexico

  16. MacGregor TR, Sabo JP, Norris SH, et al. Pharmacokinetic characterization of different dose combinations of coadministered tipranavir and ritonavir in healthy volunteers. HIV Clin Trials 2004 Dec; 5(6): 371–82

    Article  PubMed  Google Scholar 

  17. Baldwin JR, Borin MT, Wang Y, et al. Effects of food and antacid on bioavailability of the protease inhibitor PNU-140690 in healthy volunteers [abstract no. 649]. 5th Conference on Retroviruses and Opportunistic Infection; 1998 Feb 1–5; Chicago (IL)

  18. Valdez H, Sabo J, Wrack J, et al. Tipranavir (TPV) excretion mass balance and metabolite profile when coadministered with ritonavir (r) [abstract no. A-455 plus poster]. 44th ICAAC; 2004 Oct 30–Nov 2; Washington, DC, 17

  19. Yong C-L, Sabo J, Oksala C, et al. Population pharmacokinetic assessment of systemic steady-state tipranavir concentrations for adults administered tipranavir/ritonavir 500/200mg twice daily [abstract no. 654 plus poster]. 12th Conference on Retroviruses and Opportunistic Infections; 2005 Feb 22–25, Boston [online]. Available from URL: http://www.retroconference.org [Accessed 2005 Mar 4]

  20. Valdez H, McCallister SM, Hall DB. Most highly treatment-experienced recipients of tipranavir/ritonavir (TPV/r) achieve inhibitory quotients (IQ) that are associated with large week 24 viral load (VL) reductions [abstract no. 039 plus presentation]. HIV DART; 2004 Dec 12–16; Montego Bay, Jamaica

  21. Cooper C, van Heeswijk R, Bilodeau M, et al. The pharmacokinetics (PK) of single-dose and steady-state Tipranavir/Ritonavir (TPV/r) 500mg/200mg in subjects with mild or moderate hepatic impairment [abstract no. 45 plus poster no. 3.11]. 6th International Workshop on Clinical Pharmacology of HIV Therapy; 2005 Apr 28–30; Quebec City [online]. Available from URL: http://www.hivpresentation.com [Accessed 2005 Jun 16]

  22. van Heeswijk R, Sabo JP, MacGregor TR, et al. The effect of tipranavir/ritonavir 500/200 mg bid (TPV/r) on the pharmacokinetics of fluconazole in healthy volunteers [abstract no. 4.8 plus poster]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

  23. van Heeswijk R, Sabo J, MacGregor T, et al. The effect of tipranavir/ritonavir 500/200mg bid (TPV/r) on the pharmacokinetics (PK) of clarithromycin (CLR) in healthy volunteers [abstract no. A-457]. 44th ICAAC 2004 Oct 30–Nov 2; Washington, DC [online]. Available from URL: http://www.abstractsonline.com [Accessed 2005 Mar 3]

  24. van Heeswijk R, Sabo JP, Cooper C, et al. The pharmacokinetic interactions between tipranavir/ritornavir 500/200 mg bid (TPV/r) and atorvastatin, antacid, and CYP3A4 in healthy adult volunteers [abstract no 5.2 plus poster]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome

  25. van Heeswijk R, Sabo J, MacGregor T, et al. The pharmacokinetic (PK) interaction between single-dose rifabutin (RFB) and steady-state tipranavir/ritonavir 500/200 mg bid (TPV/r) in healthy volunteers [abstract no. A-456]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 Oct 30–Nov 2; Washington, DC [online]. Available from URL: http://www.abstractsonline.com [Accessed 2005 Mar 4]

  26. Goebel FD, Sabo JP, MacGregor TR, et al. Pharmacokinetic drug interaction screen of three doses of tipranavir/ritonavir (TPV/r) in HIV-infected patients on stable highly active antiretroviral therapy (HAART) [abstract plus poster]. HIV DART; 2002 Dec 15–19; Naples (FL)

  27. Roszko PJ, Curry K, Braxzina B, et al. Standard doses of efavirenz (EFV), zidovudine (ZDV), tenofovir (TDF) and didanoside (ddI) may be given with tipranavir/ritonavir (TPV/r) [abstract no. 865]. Antiviral ther 2003; 8 Suppl. 1: S248. Plus poster presented at the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment; 2003 Jul 13–16; Paris

  28. Leith J, Walmsley S, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI1182.51 [abstract]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome [online]. Available from URL: http:// www.hivpresentation.com [Accessed 2005 Feb 4]

  29. Curry K, Samuels C, Leith J, et al. Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone or in combination with saquinavir (SQV), amprenavir (APV), or lopinavir (LPV): interim analysis of BI1182.51 [presentation]. 5th International Workshop on Clinical Pharmacology of HIV Therapy; 2004 Apr 1–3; Rome [online]. Available from URL: http://www.hivpresentation.com [Accessed 2005 Feb 4]

  30. Hicks C. RESIST-1: a phase 3, randomized, controlled, open-label, multicenter trial comparing tipranavir/ritonavir (TPV/r) to an optimized comparator protease inhibitor/r (CPI/r) regimen in antiretroviral (ARV) experienced patients: 24-week data [abstract no. H-1137a plus presentation]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 Oct 31–Nov 2; Washington, DC [online]. Available from URL: http://www.medadvocates.org [Accessed 2005 Feb17]

  31. Cahn P. 24-week data from RESIST-2: phase 3 study of the efficacy and safety of either tipranavir/ritonavir (TPV/r) or an optimized ritonavir (RTV)-boosted standard-of-care (SOC) comparator PI (CPI) in a large randomized multicenter trial in treatment-experienced HIV+ patients [abstract no. PL 14.3 plus presentation]. 7th International Congress on Drug Therapy in HIV Infection; 2004 Nov 14–18; Glasgow [online]. Available from URL: http://www.abstracts2view.com [Accessed 2005 Jan 24]

  32. McCallister S, Kohlbrenner VM, Villacian J, et al. Twenty-four week combined analysis of the tipranavir (TPV) RESIST studies of 1483 treatment-experienced patients given either tipranavir/ritonavir (TPV/r) or an optimized standard of care regimen using one of four ritonavir-boosted comparator PIs (CPI/r) [abstract no. 60 plus presentation]. HIV DART; 2004 Dec 12–16; Montego Bay, Jamaica

  33. Schapiro J, Cahn P, Trottier B, et al. Effect of baseline genotype on response to tipranavir/ritonavir (TPV/r) compared with standard-of-care comparator (CPI/r) in treatment-experienced patients: the phase 3 RESIST-1 and -2 trials [abstract no. 104 plus presentation]. 12th Conference on Retroviruses and Opportunistic Infections; 2005 Feb 22–25; Boston [online]. Available from URL: http://www.retroconference.org [Accessed 2005 Mar 3]

  34. Cooper D, Hicks C, Cahn P, et al. 24-week RESIST study analyses: the efficacy of tipranavir/ritonavir (TPV/r) is superior to lopinavir/ritonavir (LPV/r), and the TPV/r treatment response is enhanced by inclusion of genotypically active antiretrovirals in the optimized background regimen (OBR). [abstract no. 560 plus poster]. 12th Conference on Retroviruses and Opportunistic Infections; 2005 Feb 22–25; Boston [online]. Available from URL: http://www.retroconference.org [Accessed 2005 Mar 4]

  35. Wu A, Huang IC, Lobo F, et al. Health-related quality of life with tipranavir in combination with an optimized background regimen in 2 randomized clinical trials [abstract no. 617 plus poster]. 12th Conference on Retroviruses and Opportunistic Infections; 2005 Feb 22–25; Boston [online]. Available from URL: http://www.retroconference.org/2005 [Accessed 2005 Mar 4]

  36. Data on file, Phase Five Communications, New York, 2005

  37. Kohlbrenner V, Gathe J, Pierone G, et al. Tipranavir/ritonavir (TPV/r) demonstrates potent efficacy in multiple protease inhibitor (PI)-experienced patients at 24 weeks: BI 1182.52 [abstract no. 7.2/2 plus poster]. 9th European AIDS Conference and 1st EACS Resistance and Pharmacology Workshop; 2003 Oct 25–29; Warsaw, 47

  38. Squires K, McCallister S, Lazzarin A, et al. Tipranavir/ritonavir (TPV/r) demonstrates a robust resistance profile in multiple protease inhibitor-experienced patients: correlation of baseline genotype and antiviral activity in BI 1182.52 [abstract no. 812]. Antiviral Ther 2003; 8 Suppl. 1: S412. Plus poster presented at the 2nd IAS Conference on HIV Pathogenesis and Treatment; 2003 Jul 13–16; Paris

    Google Scholar 

  39. Cooper D, Hall D, Jayaweera D, et al. Baseline phenotypic suceptibility to tipranavir/ritonavir is retained in isolates from patients with multiple protease inhibitor experience (BI 1182.52) [abstract no. 596 plus poster]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston (MA)

  40. Valdez H, Hall DB, Kohlbrenner VM, et al. Non-response to tipranavir is associated with pre-treatment resistance characterized by tipranavir phenotype or genotypic tipranavir score. Antiviral Ther 2005; 10 Suppl. 1: S29

    Google Scholar 

  41. Boehringer Ingelheim Pharmaceuticals Inc. US FDA approves new anti-HIV drug Aptivus for use in combination therapy, 2005 Jun 23 [online]. Available from URL: http://www.us.boehringer-ingelheim.com [Accessed 2005 Jun 29]

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Katherine F. Croom & Susan J. Keam

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  1. Katherine F. Croom
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Correspondence to Katherine F. Croom.

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Croom, K.F., Keam, S.J. Tipranavir. Drugs 65, 1669–1677 (2005). https://doi.org/10.2165/00003495-200565120-00005

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