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

Abstract

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. 99mTc-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 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