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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

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A Letter to the Editor to this article was published on 13 May 2016

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.

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Acknowledgments

With sadness, we acknowledge the remarkable contributions of Dr Robert Arceci to our understanding of multidrug resistance and to the field of Pediatric Oncology.

Funding

The research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Author information

Authors and Affiliations

  1. The Children’s Hospital of Philadelphia, The Perelman School of Medicine at The University of Pennsylvania, CTRB 4016, 3501 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Elizabeth Fox & Frank M. Balis

  2. The Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA

    Brigitte C. Widemann & Diane Cole

  3. Department of Pediatrics, Vanderbilt Medical School, Nashville, TN, USA

    Devang Pastakia

  4. Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    Clara C. Chen

  5. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    Sherry X. Yang

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  1. Elizabeth Fox
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Correspondence to Elizabeth Fox.

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Fox, E., Widemann, B.C., Pastakia, D. et al. 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. Cancer Chemother Pharmacol 76, 1273–1283 (2015). https://doi.org/10.1007/s00280-015-2845-1

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