Cancer Chemotherapy and Pharmacology

, Volume 76, Issue 6, pp 1273–1283

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

DOI: 10.1007/s00280-015-2845-1

Cite this article as:
Fox, E., Widemann, B.C., Pastakia, D. et al. Cancer Chemother Pharmacol (2015) 76: 1273. doi:10.1007/s00280-015-2845-1

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)

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