| Title |
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
|
|---|---|
| Published in |
Cancer Chemotherapy and Pharmacology, October 2015
|
| DOI | 10.1007/s00280-015-2845-1 |
| Pubmed ID | |
| Authors |
Elizabeth Fox, Brigitte C. Widemann, Devang Pastakia, Clara C. Chen, Sherry X. Yang, Diane Cole, Frank M. Balis |
| Abstract |
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. 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. 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. 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. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 71 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 71 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Master | 11 | 15% |
| Researcher | 9 | 13% |
| Student > Bachelor | 7 | 10% |
| Student > Ph. D. Student | 7 | 10% |
| Other | 6 | 8% |
| Other | 12 | 17% |
| Unknown | 19 | 27% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 16 | 23% |
| Biochemistry, Genetics and Molecular Biology | 11 | 15% |
| Pharmacology, Toxicology and Pharmaceutical Science | 6 | 8% |
| Agricultural and Biological Sciences | 5 | 7% |
| Psychology | 4 | 6% |
| Other | 8 | 11% |
| Unknown | 21 | 30% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 24 October 2015.
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#21,164,509
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Outputs from Cancer Chemotherapy and Pharmacology
#2,211
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#239,574
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Outputs of similar age from Cancer Chemotherapy and Pharmacology
#21
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