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

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.

Fig. 1

Chemotherapy schema. Chemotherapy was doxorubicin 50 mg/m²/dose IV over 15 min once per cycle, docetaxel 75 mg/m²/dose IV over 60 min once per cycle, or vinorelbine 20 mg/m²/dose IV over 10 min weekly 2× doses per cycle

Fig. 2

Rhodamine assay using flow cytometry to measure the intracellular rhodamine fluorescence in CD56+ staining cells. Dot plots of a patient’s cells at a baseline, b 24 h after systemic administration of 2 mg/kg of tariquidar, and c control (patient’s blood exposed ex vivo to 3 μM tariquidar for 1 h) are presented. CD56+ cells are in the upper portion of the graph (positive in FL2), and the intracellular rhodamine content is plotted on the FL1 axis. A histogram d of the mean fluorescent intensity of intracellular rhodamine (FL1) is presented at a baseline, b 24 h after systemic administration of tariquidar, and c control. For each patient, percent inhibition as a function of tariquidar dose is plotted and a maximum effect model of drug effect is fit to the data (e). Percent inhibition of Pgp in the rhodamine assay is dose dependent. At the 2 mg/kg dose level, the median percent inhibition was 77 %. The maximum effect model predicts maximal inhibition of 80 %

Fig. 3

Subject 009, a 2-year-old female with recurrent pancreatoblastoma, had recurrent tumor in liver (abdominal CT baseline, a), and a complete radiographic and clinical response was confirmed after 16 cycles of tariquidar in combination with vinorelbine (b). c Immunohistochemistry staining for Pgp at initial diagnosis and at relapse prior to enrollment on this study (d) in this subject. This subject completed 31 cycles of therapy without cumulative toxicity and remains free of disease more than 5 year after completion of therapy