Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 4, pp 827–833 | Cite as

Pilot study evaluating the interaction between paclitaxel and protease inhibitors in patients with human immunodeficiency virus-associated Kaposi’s sarcoma: an Eastern Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium (AMC) trial

  • Mary Cianfrocca
  • Sandra Lee
  • Jamie Von Roenn
  • Michelle A. Rudek
  • Bruce J. Dezube
  • Susan E. Krown
  • Joseph A. Sparano
Original Article



Paclitaxel, a cytotoxic agent metabolized by cytochrome P450 hepatic enzymes, is active for the treatment of human immunodeficiency (HIV) associated Kaposi’s sarcoma. Protease inhibitors are commonly used to treat HIV infection and are known to inhibit cytochrome P450. We sought to determine whether protease inhibitors alter the pharmacokinetics of paclitaxel.


Patients with advanced HIV-associated KS received paclitaxel (100 mg/m2) by intravenous infusion over 3 h, and plasma samples were collected to measure paclitaxel concentration. The area under the curve (AUC) was calculated using a combination of the log and linear trapezoidal rule, and clearance was calculated as the dose/AUC. Pharmacokinetics were compared with respect to antiretroviral therapy and toxicity,


Thirty-four patients received paclitaxel, of whom 20 had no prior paclitaxel therapy and were assessable for response. Twenty-seven had pharmacokinetic studies performed. Paclitaxel exposure was higher in patients taking protease inhibitors compared to those who were not taking protease inhibitors. The increased exposure did not correlate with efficacy or toxicity. Of the 20 patients assessable for response, 6 (30%) had an objective response and median progression-free survival was 7.8 months (95% confidence interval, 5.6, 21.0 months).


Despite higher exposure to paclitaxel, patients on protease inhibitors did not experience enhanced toxicity or efficacy.


HIV infection AIDS Kaposi’s sarcoma Paclitaxel Protease inhibitors 


  1. 1.
    Biggar RJ, Rosenberg PS, Cote T (1996) Kaposi’s sarcoma, non-Hodgkin’s lymphoma following the diagnosis of AIDS. Multistate AIDS/cancer match study group. Int J Cancer 68:754–758PubMedCrossRefGoogle Scholar
  2. 2.
    Moore PS, Chang Y (1995) Detection of herpesvirus-like DNA sequences in Kaposi’s sarcoma in patients with and without HIV infection. N Engl J Med 332:1181–1185PubMedCrossRefGoogle Scholar
  3. 3.
    Chang Y, Cesarman E, Pessin MS et al (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869PubMedCrossRefGoogle Scholar
  4. 4.
    Masood R, Cai J, Zheng T, Smith DL, Naidu Y, Gill PS (1997) Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl Acad Sci USA 94:979–984PubMedCrossRefGoogle Scholar
  5. 5.
    Montaner S (2007) Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi’s sarcoma. Cell Cycle 6:438–443PubMedCrossRefGoogle Scholar
  6. 6.
    Zeng Y, Zhang X, Huang Z et al (2007) Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi’s sarcoma-associated herpesvirus: role of JAK/STAT signaling. J Virol 81:2401–2417PubMedCrossRefGoogle Scholar
  7. 7.
    Aoki Y, Tosato G (2004) HIV-1 Tat enhances Kaposi sarcoma-associated herpesvirus (KSHV) infectivity. Blood 104:810–814PubMedCrossRefGoogle Scholar
  8. 8.
    Deregibus MC, Cantaluppi V, Doublier S et al (2002) HIV-1-Tat protein activates phosphatidylinositol 3-kinase/AKT-dependent survival pathways in Kaposi’s sarcoma cells. J Biol Chem 277:25195–25202PubMedCrossRefGoogle Scholar
  9. 9.
    Ho DD (1995) Time to hit HIV, early and hard. N Engl J Med 333:450–451PubMedCrossRefGoogle Scholar
  10. 10.
    Palella FJ Jr, Delaney KM, Moorman AC et al (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators. N Engl J Med 338:853–860PubMedCrossRefGoogle Scholar
  11. 11.
    Jacobson LP, Yamashita TE, Detels R et al (1999) Impact of potent antiretroviral therapy on the incidence of Kaposi’s sarcoma and non-Hodgkin’s lymphomas among HIV-1-infected individuals. Multicenter AIDS cohort study. J Acquir Immune Defic Syndr 21(Suppl 1):S34–S41PubMedGoogle Scholar
  12. 12.
    Flexner C (1998) HIV-protease inhibitors. N Engl J Med 338:1281–1292PubMedCrossRefGoogle Scholar
  13. 13.
    Mastrolorenzo A, Rusconi S, Scozzafava A, Barbaro G, Supuran CT (2007) Inhibitors of HIV-1 protease: current state of the art 10 years after their introduction. From antiretroviral drugs to antifungal, antibacterial and antitumor agents based on aspartic protease inhibitors. Curr Med Chem 14:2734–2748PubMedCrossRefGoogle Scholar
  14. 14.
    Dixit V, Hariparsad N, Li F, Desai P, Thummel KE, Unadkat JD (2007) Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Dispos 35:1853–1859PubMedCrossRefGoogle Scholar
  15. 15.
    Jackson A, Taylor S, Boffito M (2004) Pharmacokinetics and pharmacodynamics of drug interactions involving HIV-1 protease inhibitors. AIDS Rev 6:208–217PubMedGoogle Scholar
  16. 16.
    Malaty LI, Kuper JJ (1999) Drug interactions of HIV protease inhibitors. Drug Saf 20:147–169PubMedCrossRefGoogle Scholar
  17. 17.
    Tulpule A, Groopman J, Saville MW et al (2002) Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 95:147–154PubMedCrossRefGoogle Scholar
  18. 18.
    Gill PS, Tulpule A, Espina BM et al (1999) Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 17:1876–1883PubMedGoogle Scholar
  19. 19.
    Welles L, Saville MW, Lietzau J et al (1998) Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol 16:1112–1121PubMedGoogle Scholar
  20. 20.
    Saville MW, Lietzau J, Pluda JM et al (1995) Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet 346:26–28PubMedCrossRefGoogle Scholar
  21. 21.
    Harris JW, Rahman A, Kim BR, Guengerich FP, Collins JM (1994) Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 54:4026–4035PubMedGoogle Scholar
  22. 22.
    Sparreboom A, van Asperen J, Mayer U et al (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94:2031–2035PubMedCrossRefGoogle Scholar
  23. 23.
    Sonnichsen DS, Relling MV (1994) Clinical pharmacokinetics of paclitaxel. Clin Pharmacokinet 27:256–269PubMedCrossRefGoogle Scholar
  24. 24.
    Sonnichsen DS, Hurwitz CA, Pratt CB, Shuster JJ, Relling MV (1994) Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors. J Clin Oncol 12:532–538PubMedGoogle Scholar
  25. 25.
    Mielke S, Sparreboom A, Steinberg SM et al (2005) Association of Paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer. Clin Cancer Res 11:4843–4850PubMedCrossRefGoogle Scholar
  26. 26.
    Gianni L, Kearns CM, Giani A et al (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13:180–190PubMedGoogle Scholar
  27. 27.
    Mielke S, Sparreboom A, Behringer D, Mross K (2005) Paclitaxel pharmacokinetics and response to chemotherapy in patients with advanced cancer treated with a weekly regimen. Anticancer Res 25:4423–4427PubMedGoogle Scholar
  28. 28.
    Huizing MT, Giaccone G, van Warmerdam LJ et al (1997) Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European cancer centre. J Clin Oncol 15:317–329PubMedGoogle Scholar
  29. 29.
    Sparreboom A, Verweij J (2003) Paclitaxel pharmacokinetics, threshold models, and dosing strategies. J Clin Oncol 21:2803–2804 author reply 2805-6PubMedCrossRefGoogle Scholar
  30. 30.
    Nannan Panday VR, Hoetelmans RM, van Heeswijk RP et al (1999) Paclitaxel in the treatment of human immunodeficiency virus 1-associated Kaposi’s sarcoma–drug-drug interactions with protease inhibitors and a nonnucleoside reverse transcriptase inhibitor: a case report study. Cancer Chemother Pharmacol 43:516–519PubMedCrossRefGoogle Scholar
  31. 31.
    Duchin K, Sun J, Tan M, Ilaw M, Cabriales S, Espina BM, East D, Tulpule A, Gill PS 1997 Pharmacokinetics of low-dose Paxene (paclitaxel) in patients with refractory or relapsed AIDS-related Kaposi’s sarcoma. Proc Am Soc Clin. 15 Abstract 235Google Scholar
  32. 32.
    Cianfrocca M, Cooley TP, Lee JY et al (2002) Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi’s sarcoma: a phase I AIDS malignancy consortium study. J Clin Oncol 20:153–159PubMedCrossRefGoogle Scholar
  33. 33.
    Sparreboom A, de Bruijn P, Nooter K, Loos WJ, Stoter G, Verweij J (1998) Determination of paclitaxel in human plasma using single solvent extraction prior to isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Sci Appl 705:159–164PubMedCrossRefGoogle Scholar
  34. 34.
    Krown SE, Metroka C, Wernz JC (1989) Kaposi’s sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS clinical trials group oncology committee. J Clin Oncol 7:1201–1207PubMedGoogle Scholar
  35. 35.
    Pantanowitz L, Schlecht HP, Dezube BJ (2006) The growing problem of non-AIDS-defining malignancies in HIV. Curr Opin Oncol 18:469–478PubMedCrossRefGoogle Scholar
  36. 36.
    Martin-Carbonero L, Barrios A, Saballs P et al (2004) Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi’s sarcoma. Aids 18:1737–1740PubMedCrossRefGoogle Scholar
  37. 37.
    Fumagalli L, Zucchetti M, Parisi I et al (2000) The pharmacokinetics of liposomal encapsulated daunorubicin are not modified by HAART in patients with HIV-associated Kaposi’s sarcoma. Cancer Chemother Pharmacol 45:495–501PubMedCrossRefGoogle Scholar
  38. 38.
    Kappelhoff BS, Huitema AD, Mairuhu AT, Schellens JH, Beijnen JH (2005) No pharmacokinetic drug-drug interaction between nevirapine and paclitaxel. Anticancer Drugs 16:627–630PubMedCrossRefGoogle Scholar
  39. 39.
    Ratner L, Lee J, Tang S et al (2001) Chemotherapy for human immunodeficiency virus-associated non-hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 19:2171–2178PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Mary Cianfrocca
    • 1
  • Sandra Lee
    • 2
  • Jamie Von Roenn
    • 1
  • Michelle A. Rudek
    • 3
  • Bruce J. Dezube
    • 4
  • Susan E. Krown
    • 5
  • Joseph A. Sparano
    • 6
  1. 1.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Dana-Farber Cancer InstituteBostonUSA
  3. 3.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  4. 4.Beth Israel Deaconess Medical CenterBostonUSA
  5. 5.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Montefiore-Einstein Cancer CenterAlbert Einstein College of MedicineBronxUSA

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