Open AccessA Pharmacodynamic Study of the P‐glycoprotein Antagonist CBT‐1® in Combination With Paclitaxel in Solid Tumors
Author(s) -
Kelly Ronan J.,
Robey Robert W.,
Chen Clara C.,
Draper Deborah,
Luchenko Victoria,
Barnett Daryl,
Oldham Robert K.,
Caluag Zinnah,
Frye A. Robin,
Steinberg Seth M.,
Fojo Tito,
Bates Susan E.
Publication year - 2012
Publication title -
the oncologist
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.176
H-Index - 164
eISSN - 1549-490X
pISSN - 1083-7159
DOI - 10.1634/theoncologist.2012-0080
Subject(s) - medicine , paclitaxel , p glycoprotein , pharmacology , pharmacokinetics , pharmacodynamics , peripheral blood mononuclear cell , area under the curve , gastroenterology , efflux , cancer , multiple drug resistance , in vitro , drug resistance , biochemistry , chemistry , genetics , microbiology and biotechnology , biology
Background. This pharmacodynamic trial evaluated the effect of CBT‐1® on efflux by the ATP binding cassette (ABC) multidrug transporter P‐glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT‐1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT‐1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. Methods. CBT‐1® was dosed at 500 mg/m 2 for 7 days; a 3‐hour infusion of paclitaxel at 135 mg/m 2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT‐1® administration and on day 6 prior to the paclitaxel infusion. 99m Tc‐sestamibi imaging was performed on the same schedule. The area under the concentration–time curve from 0–3 hours (AUC 0‐3 ) was determined for 99m Tc‐sestamibi. Results. Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56 + PBMCs was a statistically significant 51%–100% lower ( p < .0001) with CBT‐1®. Among 10 patients who completed imaging, the 99m Tc‐sestamibi AUC 0‐3 for liver (normalized to the AUC 0‐3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT‐1® administration. Lung uptake was not changed. Conclusion. CBT‐1® is able to inhibit Pgp‐mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT‐1® to evaluate its ability to modulate drug uptake in tumor tissue.