Cancer Chemotherapy and Pharmacology

, Volume 76, Issue 6, pp 1273–1283 | Cite as

Pharmacokinetic and pharmacodynamic study of tariquidar (XR9576), a P-glycoprotein inhibitor, in combination with doxorubicin, vinorelbine, or docetaxel in children and adolescents with refractory solid tumors

  • Elizabeth Fox
  • Brigitte C. Widemann
  • Devang Pastakia
  • Clara C. Chen
  • Sherry X. Yang
  • Diane Cole
  • Frank M. Balis
Original Article

Abstract

Purpose

P-glycoprotein (Pgp), an ATP-dependent transport protein, confers multidrug resistance in cancer cells. Tariquidar binds and inhibits Pgp. To assess the toxicity, pharmacokinetics (PK), and pharmacodynamics of tariquidar, we conducted a phase I trial of tariquidar in combination with doxorubicin, docetaxel, or vinorelbine in children and adolescents with recurrent or refractory solid tumors.

Methods

Patients less than 19 years of age with refractory or recurrent solid tumors were eligible. Tariquidar (1, 1.5, or 2 mg/kg) was administered alone and in combination with doxorubicin, docetaxel, or vinorelbine. PK of tariquidar and cytotoxic drugs was performed. Pgp function was assessed by a rhodamine efflux assay and 99mTc-sestamibi scintigraphy. Tumor Pgp expression was assessed by immunohistochemistry. Response was assessed using Response Evaluation Criteria in Solid Tumors.

Results

Twenty-nine subjects were enrolled. No tariquidar-related dose-limiting toxicity (DLT) was observed. DLT related to cytotoxic drugs occurred in 12 % of subjects receiving tariquidar 2 mg/kg. When administered in combination with tariquidar, the clearance of docetaxel and vinorelbine was reduced compared to prior studies. Inhibition of rhodamine efflux was dose dependent. After tariquidar administration, 99mTc-sestamibi accumulation in tumor increased by 22 %. Objective responses (1 complete, 2 partial) were observed. There was no association between tumor Pgp expression and response.

Conclusion

A tolerable and biologically active dose of tariquidar was established in children and adolescents. This trial demonstrates that modulators of resistance can be evaluated in combination with chemotherapy, and pharmacokinetic and pharmacodynamic endpoints can be useful in determination of recommended dose in children and adolescents.

Keywords

Multidrug resistance P-glycoprotein Pediatric cancer Phase I Pharmacokinetics 

Supplementary material

280_2015_2845_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 22 kb)

References

  1. 1.
    Abraham EH, Prat AG, Gerweck L, Seneveratne T, Arceci RJ, Kramer R, Guidotti G, Cantiello HF (1993) The multidrug resistance (mdr1) gene product functions as an ATP channel. Proc Natl Acad Sci U S A 90:312–316CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Abraham J, Edgerly M, Wilson R, Chen C, Rutt A, Bakke S, Robey R, Dwyer A, Goldspiel B, Balis F, Van Tellingen O, Bates SE, Fojo T (2009) A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine. Clin Cancer Res 15:3574–3582CrossRefPubMedGoogle Scholar
  3. 3.
    Agrawal M, Abraham J, Balis FM, Edgerly M, Stein WD, Bates S, Fojo T, Chen CC (2003) Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576. Clin Cancer Res 9:650–656PubMedGoogle Scholar
  4. 4.
    Arceci RJ (1993) Clinical significance of P-glycoprotein in multidrug resistance malignancies. Blood 81:2215–2222PubMedGoogle Scholar
  5. 5.
    Arceci RJ (2000) Can multidrug resistance mechanisms be modified? Br J Haematol 110:285–291CrossRefPubMedGoogle Scholar
  6. 6.
    Bauer M, Karch R, Zeitlinger M, Stanek J, Philippe C, Wadsak W, Mitterhauser M, Jager W, Haslacher H, Muller M, Langer O (2013) Interaction of 11C-tariquidar and 11C-elacridar with P-glycoprotein and breast cancer resistance protein at the human blood–brain barrier. J Nucl Med 54:1181–1187CrossRefPubMedGoogle Scholar
  7. 7.
    Bauer M, Zeitlinger M, Todorut D, Bohmdorfer M, Muller M, Langer O, Jager W (2013) Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects. Pharmacology 91:12–19CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Blaney SM, Seibel NL, O’Brien M, Reaman GH, Berg SL, Adamson PC, Poplack DG, Krailo MD, Mosher R, Balis FM (1997) Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children’s Cancer Group trial. J Clin Oncol 15:1538–1543PubMedGoogle Scholar
  9. 9.
    Boote DJ, Dennis IF, Twentyman PR, Osborne RJ, Laburte C, Hensel S, Smyth JF, Brampton MH, Bleehen NM (1996) Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer. J Clin Oncol 14:610–618PubMedGoogle Scholar
  10. 10.
    Bradshaw DM, Arceci RJ (1998) Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J Clin Oncol 16:3674–3690PubMedGoogle Scholar
  11. 11.
    Chan HS, Grogan TM, DeBoer G, Haddad G, Gallie BL, Ling V (1996) Diagnosis and reversal of multidrug resistance in paediatric cancers. Eur J Cancer 32A:1051–1061CrossRefPubMedGoogle Scholar
  12. 12.
    Clarke SJ, Rivory LP (1999) Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet 36:99–114CrossRefPubMedGoogle Scholar
  13. 13.
    Deuchars KL, Ling V (1989) P-glycoprotein and multidrug resistance in cancer chemotherapy. Semin Oncol 16:156–165PubMedGoogle Scholar
  14. 14.
    Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I (1987) Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 84:265–269CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fojo T, Bates S (2003) Strategies for reversing drug resistance. Oncogene 22:7512–7523CrossRefPubMedGoogle Scholar
  16. 16.
    Frost BM, Eksborg S, Bjork O, Abrahamsson J, Behrendtz M, Castor A, Forestier E, Lonnerholm G (2002) Pharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutional collaborative study. Med Pediatr Oncol 38:329–337CrossRefPubMedGoogle Scholar
  17. 17.
    Gardner ER, Smith NF, Figg WD, Sparreboom A (2009) Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice. J Exp Clin Cancer Res 28:99CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58CrossRefPubMedGoogle Scholar
  19. 19.
    Johansen M, Kuttesch J, Bleyer WA, Krailo M, Ames M, Madden T (2006) Phase I evaluation of oral and intravenous vinorelbine in pediatric cancer patients: a report from the Children’s Oncology Group. Clin Cancer Res 12:516–522CrossRefPubMedGoogle Scholar
  20. 20.
    Kelly RJ, Draper D, Chen CC, Robey RW, Figg WD, Piekarz RL, Chen X, Gardner ER, Balis FM, Venkatesan AM, Steinberg SM, Fojo T, Bates SE (2011) A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin Cancer Res 17:569–580CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kuhnle M, Egger M, Muller C, Mahringer A, Bernhardt G, Fricker G, Konig B, Buschauer A (2009) Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar. J Med Chem 52:1190–1197CrossRefPubMedGoogle Scholar
  22. 22.
    Larsen AK, Escargueil AE, Skladanowski A (2000) Resistance mechanisms associated with altered intracellular distribution of anticancer agents. Pharmacol Ther 85:217–229CrossRefPubMedGoogle Scholar
  23. 23.
    Martin C, Berridge G, Mistry P, Higgins C, Charlton P, Callaghan R (1999) The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol 128:403–411CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Montesinos RN, Moulari B, Gromand J, Beduneau A, Lamprecht A, Pellequer Y (2014) Coadministration of P-glycoprotein modulators on loperamide pharmacokinetics and brain distribution. Drug Metab Dispos 42:700–706CrossRefPubMedGoogle Scholar
  25. 25.
    Pajeva IK, Sterz K, Christlieb M, Steggemann K, Marighetti F, Wiese M (2013) Interactions of the multidrug resistance modulators tariquidar and elacridar and their analogues with P-glycoprotein. ChemMedChem 10:1701–1713Google Scholar
  26. 26.
    Pick A, Klinkhammer W, Wiese M (2010) Specific inhibitors of the breast cancer resistance protein (BCRP). ChemMedChem 5:1498–1505CrossRefPubMedGoogle Scholar
  27. 27.
    Pinwnica-Worms D (2000) Functional identification of multidrug resistance gene expression in vivo. Lippincott Williams & Wilkins, New OrleansGoogle Scholar
  28. 28.
    Pusztai L, Wagner P, Ibrahim N, Rivera E, Theriault R, Booser D, Symmans FW, Wong F, Blumenschein G, Fleming DR, Rouzier R, Boniface G, Hortobagyi GN (2005) Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 104:682–691CrossRefPubMedGoogle Scholar
  29. 29.
    Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, Piwnica-Worms D (1999) Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 96:3900–3905CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Robey R, Bakke S, Stein W, Meadows B, Litman T, Patil S, Smith T, Fojo T, Bates S (1999) Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833. Blood 93:306–314PubMedGoogle Scholar
  31. 31.
    Seibel NL, Blaney SM, O’Brien M, Krailo M, Hutchinson R, Mosher RB, Balis FM, Reaman GH (1999) Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: a collaborative Pediatric Oncology Branch, National Cancer Institute and Children’s Cancer Group trial. Clin Cancer Res 5:733–737PubMedGoogle Scholar
  32. 32.
    Stewart A, Steiner J, Mellows G, Laguda B, Norris D, Bevan P (2000) Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration. Clin Cancer Res 6:4186–4191PubMedGoogle Scholar
  33. 33.
    Thompson PA, Rosner GL, Matthay KK, Moore TB, Bomgaars LR, Ellis KJ, Renbarger J, Berg SL (2009) Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study. Cancer Chemother Pharmacol 64:243–251CrossRefPubMedGoogle Scholar
  34. 34.
    Witherspoon SM, Emerson DL, Kerr BM, Lloyd TL, Dalton WS, Wissel PS (1996) Flow cytometric assay of modulation of P-glycoprotein function in whole blood by the multidrug resistance inhibitor GG918. Clin Cancer Res 2:7–12PubMedGoogle Scholar
  35. 35.
    Wunder JS, Bull SB, Aneliunas V, Lee PD, Davis AM, Beauchamp CP, Conrad EU, Grimer RJ, Healey JH, Rock MJ, Bell RS, Andrulis IL (2000) MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study. J Clin Oncol 18:2685–2694PubMedGoogle Scholar
  36. 36.
    Zinzi L, Capparelli E, Cantore M, Contino M, Leopoldo M, Colabufo NA (2014) Small and innovative molecules as new strategy to revert MDR. Front Oncol 4:2CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Elizabeth Fox
    • 1
  • Brigitte C. Widemann
    • 2
  • Devang Pastakia
    • 3
  • Clara C. Chen
    • 4
  • Sherry X. Yang
    • 5
  • Diane Cole
    • 2
  • Frank M. Balis
    • 1
  1. 1.The Children’s Hospital of PhiladelphiaThe Perelman School of Medicine at The University of PennsylvaniaPhiladelphiaUSA
  2. 2.The Pediatric Oncology BranchNational Cancer InstituteBethesdaUSA
  3. 3.Department of PediatricsVanderbilt Medical SchoolNashvilleUSA
  4. 4.Department of Nuclear Medicine, Clinical CenterNational Institutes of HealthBethesdaUSA
  5. 5.Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaUSA

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