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Cancer Chemother Pharmacol. 2015 Dec;76(6):1273-83. doi: 10.1007/s00280-015-2845-1. Epub 2015 Oct 20.

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.

Author information

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. foxe@email.chop.edu.
2
The Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
3
Department of Pediatrics, Vanderbilt Medical School, Nashville, TN, USA.
4
Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
5
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
6
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.

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 (99m)Tc-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, (99m)Tc-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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00011414.

KEYWORDS:

Multidrug resistance; P-glycoprotein; Pediatric cancer; Pharmacokinetics; Phase I

PMID:
26486517
DOI:
10.1007/s00280-015-2845-1
[Indexed for MEDLINE]

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