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.
OBJECTIVE
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.


CONCLUSIONS
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.
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.
Elizabeth
E
Fox
The Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Brigitte C
BC
Widemann
Department of Pediatrics, Vanderbilt Medical School, Nashville, TN, USA.
Devang
D
Pastakia
Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Clara C
CC
Chen
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
Sherry X
SX
Yang
The Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Diane
D
Cole
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.
Frank M
FM
Balis
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000293:Adolescent; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077235:Vinorelbine; D014839:Vomiting / Q000139:chemically induced
D018435:ATP Binding Cassette Transporter, Subfamily B; D011804:Quinolines; D043823:Taxoids; D000077143:Docetaxel; D014747:Vinblastine; D004317:Doxorubicin; C402343:tariquidar; D000077235:Vinorelbine
Multidrug resistance; P-glycoprotein; Pediatric cancer; Pharmacokinetics; Phase I