nach oben

Erschienen in:

01.12.2015 | Original Article

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

verfasst von: Elizabeth Fox, Brigitte C. Widemann, Devang Pastakia, Clara C. Chen, Sherry X. Yang, Diane Cole, Frank M. Balis

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2015

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

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 90:312–316CrossRefPubMedPubMedCentral

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 15:3574–3582CrossRefPubMed

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 9:650–656PubMed

Arceci RJ (1993) Clinical significance of P-glycoprotein in multidrug resistance malignancies. Blood 81:2215–2222PubMed

Arceci RJ (2000) Can multidrug resistance mechanisms be modified? Br J Haematol 110:285–291CrossRefPubMed

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 54:1181–1187CrossRefPubMed

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 91:12–19CrossRefPubMedPubMedCentral

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 15:1538–1543PubMed

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 14:610–618PubMed

10.

Bradshaw DM, Arceci RJ (1998) Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J Clin Oncol 16:3674–3690PubMed

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:1051–1061CrossRefPubMed

12.

Clarke SJ, Rivory LP (1999) Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet 36:99–114CrossRefPubMed

13.

Deuchars KL, Ling V (1989) P-glycoprotein and multidrug resistance in cancer chemotherapy. Semin Oncol 16:156–165PubMed

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 84:265–269CrossRefPubMedPubMedCentral

15.

Fojo T, Bates S (2003) Strategies for reversing drug resistance. Oncogene 22:7512–7523CrossRefPubMed

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 38:329–337CrossRefPubMed

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 28:99CrossRefPubMedPubMedCentral

18.

Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58CrossRefPubMed

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 12:516–522CrossRefPubMed

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 17:569–580CrossRefPubMedPubMedCentral

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 52:1190–1197CrossRefPubMed

22.

Larsen AK, Escargueil AE, Skladanowski A (2000) Resistance mechanisms associated with altered intracellular distribution of anticancer agents. Pharmacol Ther 85:217–229CrossRefPubMed

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 128:403–411CrossRefPubMedPubMedCentral

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 42:700–706CrossRefPubMed

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 10:1701–1713

26.

Pick A, Klinkhammer W, Wiese M (2010) Specific inhibitors of the breast cancer resistance protein (BCRP). ChemMedChem 5:1498–1505CrossRefPubMed

27.

Pinwnica-Worms D (2000) Functional identification of multidrug resistance gene expression in vivo. Lippincott Williams & Wilkins, New Orleans

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 104:682–691CrossRefPubMed

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 96:3900–3905CrossRefPubMedPubMedCentral

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 93:306–314PubMed

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 5:733–737PubMed

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 6:4186–4191PubMed

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 64:243–251CrossRefPubMed

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 2:7–12PubMed

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 18:2685–2694PubMed

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 4:2CrossRefPubMedPubMedCentral

Titel: 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
verfasst von: Elizabeth Fox
Brigitte C. Widemann
Devang Pastakia
Clara C. Chen
Sherry X. Yang
Diane Cole
Frank M. Balis
Publikationsdatum: 01.12.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2015
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2845-1

Springer Medizin

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