If approved, tipranavir (Boehringer Ingelheim) will be the ninth protease inhibitor (PI) available and the first nonpeptidic PI available in the United States. Designed by structure-based analysis, tipranavir is more flexible at the binding site, allowing for a potent and durable antiretroviral response. The tipranavir (TPV) and ritonavir (RTV) PI regimen (TPV/r) studied in clinical trials had a moderate pill burden, requiring 4 pills to be taken twice daily (2 RTV 100 mg and 2 TPV 250 mg).
Abstract If approved, tipranavir (Boehringer Ingelheim) will be the ninth protease inhibitor (PI) available and the first nonpeptidic PI available in the United States. Designed by structure-based analysis, tipranavir is more flexible at the binding site, allowing for a potent and durable antiretroviral response. The tipranavir (TPV) and ritonavir (RTV) PI regimen (TPV/r) studied in clinical trials had a moderate pill burden, requiring 4 pills to be taken twice daily (2 RTV 100 mg and 2 TPV 250 mg). In phase 3 clinical studies, TPV/r provided enhanced immunologic and virologic responses versus comparator PI and ritonavir regimens. Resistance to tipranavir was uncommon, even among PI-resistant isolates. Decreased virologic response to TPV/r has been infrequent and has usually been observed when greater than 2 primary PI mutations were present. Further, treatment with tipranavir did not appear to alter viral resistance to other PIs. The adverse effects associated with tipranavir appear similar to those of other PIs, including nausea, vomiting, and diarrhea, as well as hepatic and metabolic laboratory abnormalities. (Formulary. 2005;40:104-113.)
More people are living with human immunodeficiency virus (HIV) today than ever before, with almost 5 million people worldwide acquiring the disease in 2004.1 Recent reports estimate that 1 millionpeople in the United States and 39.4 million people in the world are infected with the virus.1 The overall goals of HIV therapy are suppression of viral load, preservation of immune function, and prevention of disease-associated morbidity and mortality.2 "Potent combination antiretroviral therapy" utilizing at least 3 drugs, including 2 nucleoside (nucleotide) reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), has resulted in regimens that are capable of achieving improved HIV therapy outcomes.2 The most effective viral response is seen when patients are at least 90%-95% adherent to antiretroviral regimens.3 Unfortunately, many of these regimens are difficult to adhere to due to high pill burden and complex dosing schedules, resulting in decreased efficacy and increased viral resistance.2
CHEMISTRY AND PHARMACOLOGY Tipranavir disodium (C31H31F3N2 Na2O5S), previously known as PNU-140690, is currently under FDA review. Tipranavir has a chemical structure of [R-(R*,R*)]-N-[3-[1-[5,6- dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3- yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide di-sodium salt with a molecular weight of 646.64 d.5
Tipranavir, similarly to other PIs, inhibits the production of mature viral components by binding to the HIV-1 protease's active site, preventing the processing of viral gag and gag-pol polyprotein precursors.6 Tipranavir was designed by structure-based analysis and has a structure more adaptable to alterations in the conformation of the protease's binding site than the currently available PIs.7 This increased flexibility at the binding site is thought to be at least one of the reasons for tipranavir's strong response against even multiple-PI-resistant viruses.7
Tipranavir, like most available PIs, is lipophilic, resulting in poor solubility, impaired bioavailability, and thus a large pill burden.8 Tipranavir's pill burden was initially large, requiring between 4 and 8 capsules twice a day; however, this burden was decreased as the original hard-filled 300-mg capsules (HFC) were changed during phase 2 development to a 250-mg self-emulsifying drug delivery system (SEDDS) soft-gelatin capsule.8,9 This SEDDS formulation improved the dissolution and bioavailability of tipranavir, resulting in a 2-fold increase in systemic concentrations and thereby cutting tipranavir pill burden in half.8-10
RESISTANCE ANALYSIS Many studies have investigated correlations between tipranavir and resistance to HIV-1. Initial in vitro data assessed tipranavir resistance in 10 viral isolates obtained from multiple-PI-resistant (including indinavir [IDV], saquinavir [SQV], and RTV) patients failing their current therapy.15 The IC90, or concentration that inhibits 90% of isolated HIV from these multiple-PI-resistant patients, was £0.9 µM (range 0.3-0.9 M). After in vitro tipranavir exposure, mutations E35D, N37D, D60E, R41K, I15V, and A71T were observed; however, these mutations did not appear to correlate with antiviral activity.15
The effects of PI mutations on tipranavir resistance were analyzed in 134 routine clinical samples.4 Although 90% of these isolates were resistant to multiple protease inhibitors, they demonstrated a less than 4-fold increase in tipranavir IC50.4 Additionally, 19 isolates demonstrated a greater than 2.5-fold increase in sensitivity to tipranavir.4 This increased sensitivity was associated with high frequency of the G48V and V82A mutations, while tipranavir-resistant isolates commonly demonstrated V82T and I84V or I84V and 90M.4
The BI 1182.2 study evaluated PI resistance in patients receiving tipranavir. Reduced susceptibility to tipranavir was present in 1 patient (2.4%) at baseline and 5 patients (12.2%) after more than a year of tipranavir and RTV.16 Mutations at V82T plus an alteration at codon L33 (I, F, or V) were identified in 4 of the 6 patients exhibiting decreased susceptibility to tipranavir.16 Resistance to other PIs did not change over 80 weeks of tipranavir/RTV (TPV/r) therapy.16
Subjects in the BI 1182.52 study included multiple-antiretroviral-experienced patients with at least 1 primary PI mutation but not multiples from codons 82, 84, or 90.17 The median change in wild-type IC50 increased with the number of universal protease inhibitor-associated mutations (UPAM) from 1.1-fold (1 UPAM) to 2.2-fold (3 UPAM).18 The presence of 3 or more UPAMs was associated with decreased viral load response.18 In a follow-up retrospective study assessing the genotypes of 589 patients, only 5% exhibited 3 or more UPAMs.19
HIV-1 isolates and the resultant resistance mutations were analyzed in vitro via passage through increasing drug concentrations.20 In 70 passages, at tipranavir concentrations up to 20 µM, resistance was demonstrated at codons 10, 13, 3, 32, 33, 36, 45, 54, 71, 82, and 84.20 Confirming data from prior studies, no single mutation was associated with tipranavir resistance. Resistance at 1.7- and 3-fold over wild type virus was seen with combinations of 2 and 3 of the mutations, respectively. Finally, when tipranavir was combined with APV or LPV in vitro, no antagonistic effects were seen.20
Tipranavir is both a substrate and inducer of the cytochrome isoenzyme 3A4 in addition to being a glycoprotein substrate.22 RTV is a potent inhibitor of the isoenzyme 3A4 that has been used to increase or boost concentrations of PIs that are metabolized via this enzyme. RTV increased tipranavir Cmin 4-fold and maximum plasma concentration (Cmax) 20-fold.21
The Cmin values of PIs have been associated with reductions in viral loads.2 In a pharmacokinetic analysis, a Cmin above 20 µM, which is greater than 10x the concentration needed to inhibit 90% (IC90) of the multiple-PI-resistant HIV isolates, and a concentration above which was rarely needed, was achieved with TPV/r regimens of 500/100 mg twice daily or greater.21
The safety and efficacy of TPV/r was further evaluated in patients failing their first PI-containing regimen.28 Patients received 2 new NRTIs and either TPV/r 500/100 mg, TPV/r 1,250/100 mg, or SQV/r 400/400 mg twice daily for 16 weeks. Virologic and immunologic responses to therapy were similar with regard to median change in viral load, percent of patients with undetectable viral load, and median rise in CD4 cell counts. Seven patients withdrew due to an adverse event (1 in the TPV/r 500/100 mg group, 2 in the TPV/r 1,250/100 mg group, and 4 in the SQV/r group).
BI 1182.52 was a multicenter, randomized, blinded trial of 3 TPV/r-containing regimens in multiple-PI-experienced patients.31 Two hundred and sixteen patients with viral loads of at least 1,000 copies/mL and prior experience with at least 1 NRTI, 1 NNRTI, and 2 PIs were enrolled. Patients also had at least 1 PI mutation. Patients were randomized 1:1:1 to receive TPV/r 500/100 mg, 500/200 mg, or 750/200 mg bid. Virologic response was evaluated at 2 weeks and safety at 4 weeks. Baseline viral load (4.5 log10 copies/mL), CD4 cell count (153 cells/mm3), and PI experience (37% LPV and 79.6% IDV) were similar between groups. Short-term efficacy appeared similar as demonstrated by viral load reductions. Although all groups demonstrated similar virologic response, the 500/200-mg group was chosen for phase 3 study as the 500/100 mg group demonstrated low tipranavir Cmin.35
RESIST-2 provided further evidence of TPV/r efficacy in antiretroviral-experienced patients.30 RESIST-2 included 863 patients from Europe and Latin America and had a similar study design to RESIST-1. After 24 weeks of follow-up, the proportion of patients with undetectable viral loads (<400 and <50 copies/mL, P=.001), the median decreases in viral load from baseline, and the increases in CD4 cell counts from baseline (P=.02) were significantly improved in the TPV/r arm compared to those in the CPI/r arm. Therapy was discontinued due to an adverse event in 6.9% of TPV/r patients and 4.7% of CPI/r patients.
The types of adverse events that have been reported in clinical trials with tipranavir appear similar to those of other PIs. In addition to short-term adverse events, many of the PIs have also been associated with hepatotoxicity, metabolic complications, fat redistribution, and lipid abnormalities. Although no long-term studies have been conducted with TPV/r, similar types of adverse effects may be expected.2
Dr Ellis is assistant clinical professor, University of Connecticut School of Pharmacy, Storrs, Conn, and clinical pharmacy specialist, Department of Pharmacy and Division of Pediatric Infectious Diseases, Connecticut Children’s Medical Center, Hartford, Conn. She can be reached at email@example.com. Dr Ross is director of HIV Programs, Hartford Hospital, Hartford, Conn, and assistant professor of medicine, University of Connecticut School of Medicine, Farmington, Conn.
In each issue, the “Focus on” feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, director of Drug Information Services at Hartford Hospital in Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.
Editors’ note: The clinical information provided in “Focus on” articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.
REFERENCES 1. Joint United Nations Programme on HIV/AIDS(UNAIDS) and World Health Organization (WHO). AIDS epidemic update: 2004. Available at:http:// http://www.unaids.org/. Accessed December 20, 2004.
2. Panel on Clinical Practices for the Treatment of HIV infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at: http:// http://www.aidsinfo.nih.gov/. Accessed December 20, 2004.
3. Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS. 2001;15:1369-1377.
4. Larder BA, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS. 2000;14:1943-1948.
5. Drug Standards Pharmacopeial Forum. Revisions of United States Adopted Names (USAN), Tipranavir. United States Pharmacopeia website. Available at: http:// http://www.usp.org/standards/pf/2506/f01.html. Accessed February 16, 2005.
6. Flexner C. HIV-protease inhibitors. N Engl J Med. 1998;338:1281-1292.
7. Schake D. How flexible is tipranavir in complex with the HIV-1 protease active site? AIDS. 2004;18:579-580.
8. McCallister S, Valdez H, Curry K, et al. A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004;35:376-382.
9. Curry R, Markowitz M, Slater L, Neubacher D, Robinson P, Cotton G, and the BI 1182.2 Study Team. Safety and efficacy of tipranavir, a non-peptidic protease inhibitor, in multiple PI-failure patients (BI 1182.2) [abstract]. Presented at: 1st International AIDS Society Conference on HIV Pathogenesis and Treatment; July 7-11, 2001; Buenos Aires, Argentina. Abstract 3.
10. Tipranavir monograph. US Department of Health and Human Services AIDS info resource page. Available at: http://aidsinfo.nih.gov/. Accessed February 16, 2005.
11. 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;41:1058-1063.
12. Mayers DL, Kohlbrenner VM, Dohnanyil C, et al. The inhibitory quotient (IQ) of tipranavir/ritonavir (TPV/r) in triple class experienced HIV+ patients; results from BI 1182.52 [abstract]. Presented at: 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 9.
13. 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;41:2367-2373.
14. 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;53:464-468.
15. 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;44:1328-1332.
16. Schwartz R, Kazanjian P, Slater L, et al. Resistance to tipranavir is uncommon in a randomized trial of tipranavir/ritonavir (TPV/RTV) in multiple PI-failure patients (BI 1182.2) [abstract]. Presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Wash. Abstract 562.
17. 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]. Presented at: 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 13-17, 2003; Paris, France. Abstract 812.
18. Cooper D, Hall D, Jayaweera D, et al. Baseline phenotypic susceptibility to tipranavir/ritonavir (TPV/r) is retained in isolates from patients with multiple-protease inhibitor (PI) experience (BI 1182.52) [abstract]. Presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Mass. Abstract 596.
19. Miranda AC, Duque L, Carvalho AP, et al. Expected tipranavir resistance in a group of 589 patients with previous exposure to protease inhibitors [abstract]. Presented at: 2nd European HIV Drug Resistance Workshop; March 11-13, 2004; Rome, Italy. Abstract 3.6.
20. 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]. Presented at: XII International HIV Drug Resistance Workshop; June 10-14, 2003; Cabo San Lucas, Mexico. Abstract 12.
21. McCallister S, Sabo JP, Mayers DL, Galitz L. An open-label, steady-state investigation of the pharmacokinetics (PK) of tipranavir (TPV) and ritonavir (RTV) and their effects on cytochromep-450 (3A4) activity in normal, healthy volunteers (BI 1182.5)[abstract]. Presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Wash. Abstract 434W.
22. Baldwin JR, Borin MT, Ferry JJ, et al. Pharmacokinetic (PK) interaction between the HIV protease inhibitors tipranavir and ritonavir [abstract]. Presented at: 39th International Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, Calif. Abstract 657.
23. Walmsley S, Leith J, 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 BI 1182.51 [abstract]. Presented at: XV International AIDS Society Conference; July 11-16, 2004; Bangkok, Thailand. Abstract WeOr±236.
24. van Heeswijk R, Sabo JP, MacGregor TR, et al. The effect of tipranavir/ritonavir 500 mg/200 mg bid (TPV/r) on the pharmacokinetics of fluconazole in healthy volunteers [abstract]. Presented at: 5th International Workshop on Clinical Pharmacology in HIV Therapy; April 1-3, 2004; Rome, Italy. Abstract 4.8.
25. van Heeswijk R, Sabo J, MacGregor T, et al. The effect of tipranavir/ritonavir 500/200 mg bid (TPV/r) on the pharmacokinetics (PK) of clarithromycin (CLR) in healthy volunteers [abstract]. Presented at: 44th International Conference on Antimicrobial Agents and Chemotherapy; October 28-November 2, 2004; Washington, DC. Abstract A-457.
26. 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]. Presented at: 44th International Conference on Antimicrobial Agents and Chemotherapy; October 28-November 2, 2004; Washington, DC. Abstract A-456.
27. van Heeswijk R, Sabo JP, Cooper C, et al. The pharmacokinetic interactions between tipranavir/ ritonavir 500 mg/200 mg bid (TPV/r) and atorvastatin, antacid and CYP3A4 in healthy volunteers [abstract]. Presented at: 5th International Workshop on Clinical Pharmacology of HIV Therapy; April 1-3, 2004; Rome, Italy. Abstract 5.2.
28. Slater L, Farthing C, Jayaweera J, et al. Safety and efficacy of tipranavir (TPV), a novel non-peptidic protease inhibitor, plus ritonavir (RTV), in PI failure patients [abstract]. Presented at: 41st International Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, IL. Abstract LB-15.
29. Hicks C and RESIST-1 study team. 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]. Presented at: 44th International Conference on Antimicrobial Agents and Chemotherapy; October 28-November 2, 2004; Washington, DC. Abstract H-1137a.
30. Cahn P and the RESIST-2 study team. 24-week data from RESIST-2: Phase 3 study of the efficacy and safety of background therapy plus tipranavir/ritonavir (TPV/r) or optimized ritonavir boosted standard of care (SOC) comparator PI (CPI) in a large randomized multicenter trial in treatment-experienced HIV+ patients [abstract]. Presented at: 7th International Congress on Drug Therapy in HIV Infection; November 14-18, 2004; Glasgow, Scotland. Abstract PL14.3.
31. Gathe J, Kohlbrenner VM, Pierone G, et al. Tipranavir/ritonavir demonstrates potent efficacy in multiple protease inhibitor experienced patients: BI 1182.52. Presented at: 10th Conference on Retroviruses & Opportunistic Infections; February 10-14, 2003; Boston, Mass. Abstract 179.
32. Wang Y, Daenzer C, Wood R, et al, and the Tipranivir Team. The safety, efficacy, and viral dynamics analysis of tipranavir, a new-generation protease inhibitor, in a phase II study in antiretroviral-naive HIV-1 infected patients [abstract]. Presented at: 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 4, 2000; San Francisco, Calif. Abstract 673.
33. Neubacher D, Markowitz M, Slater L, et al. Long-term 80-week follow-up of highly treatment-experienced (HTE) patients on tipranavir-based antiretroviral therapy (BI 1182.2) [abstract]. Presented at: 9th European AIDS Conference; Warsaw, Poland. Abstract 7.2/3.
34. Chene G, Sterne JA, May M, et al. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet. 2003;362:679-686.
35. Yeni P, MacGregor T, Gathe J, Arasteh K, Jayaweera D, Jemsek J. Correlation of viral load reduction and plasma levels in multiple protease inhibitor (PI)-experienced patients taking tipranavir/ritonavir (TPV/r) in a phase IIB trial: BI 1182.52 [abstract]. Presented at: 10th Conference on Retroviruses & Opportunistic Infections; February 10-14, 2003; Boston, Mass. Abstract 528.
36. Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz (EFV), zidovudine (ZDV), tenofovir (TDF), and didanosine (ddI) may be given with tipranavir/ritonavir (TPV/r). Presented at: 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 865.
37. Valdez H, Sabo J, Wruck J, et al. Tipranavir (TPV) excretion mass balance and metabolite profile when coadministered with ritonavir [abstract]. Presented at: 44th International Conference on Antimicrobial Agents and Chemotherapy; October 28-November 2, 2004; Washington, DC. Abstract A-455.