A Pharmacodynamic Study of the P-glycoprotein Antagonist CBT-1 registered in Combination With Paclitaxel in Solid Tumors

Background:This pharmacodynamic trial evaluated the effect of CBT-1 registered on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1 registered 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 registered did not alter the pharmacokinetics of paclitaxel or doxorubicin.Methods:CBT-1 registered was dosed at 500 mg/m2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1 registered administration and on day 6 prior to the paclitaxel infusion. 99mTc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC0-3) was determined for 99mTc-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 registered . Among 10 patients who completed imaging, the 99mTc-sestamibi AUC0-3 for liver (normalized to the AUC0-3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT-1 registered administration. Lung uptake was not changed.Conclusion:CBT-1 registered 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 registered to evaluate its ability to modulate drug uptake in tumor tissue.Discussion:Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1-/-; p53-/- mouse model of hereditary breast cancer that