Abstract B144: Evaluation of total and encapsulated drug pharmacokinetics for BIND-014 (docetaxel nanoparticles for injectable suspension) in a phase 1 study
Authors: Summa Jason M. , Von Hoff Daniel D. , Sachdev Jasgit C. , Mita Monica M. , LoRusso Patricia M. , Eisenberg Peter D. , Burris Howard A. , Hart Lowell L. , Youssoufian Hagop , Parsons Donald M. , Low Susan C. 
Published: May 2016

Abstract
Background: BIND-014 is a novel, prostate-specific membrane antigen (PSMA) targeted AccurinTM (polymeric nanoparticle) containing docetaxel. PSMA is expressed on prostate cancer cells and on vasculature of many solid tumors. In a phase 1 study in patients with solid tumors BIND-014 was generally well-tolerated and displayed anti-tumor activity across a range of tumor types. Evaluation of total drug pharmacokinetics (PK) for BIND-014 in this study demonstrated differentiated plasma profiles compared to docetaxel, which is likely attributable to the vascular retention of the nanoparticle. Total docetaxel quantitation does not distinguish between docetaxel that remains encapsulated or that is released from the nanoparticle. Here we describe a method for separation of encapsulated docetaxel and characterization of the PK of total and encapsulated BIND-014 docetaxel in the phase 1 study.
Material and Methods: PK evaluation of BIND-014 was performed in 28 patients on Day 1 of a 21-day cycle (Q3W) over a dose range of 3.5 to 75 mg/m2. On Cycle 1, Day 1, blood was collected at pre-dose and at 30 minutes, 1, 2, 4, 6, 8, 24, 36, and 48 hours post-dose. A solid phase separation method in which released docetaxel binds to the matrix was developed for quantitation of encapsulated docetaxel. Encapsulated and total docetaxel were measured by LCMS. Peak concentration (Cmax), percent encapsulated, minimum concentration (Cmin), time to peak concentration (Tmax), area under the concentration-time curve (AUC), half-life (t1/2), clearance (CL) and volume of distribution (Vd) were determined for each patient using encapsulated and total plasma concentration data.
Results: Plasma concentrations of BIND-014 persisted for at least 48 hours at the higher dose levels. Clearance was independent of the administered dose, indicating a linear dose-concentration relationship following a single intravenous administration. Evaluation of encapsulated docetaxel plasma concentrations at all dose levels and all timepoints studied demonstrated mean values between 91% and 98% of total docetaxel, indicating that most circulating docetaxel was encapsulated in nanoparticles.
Conclusions: The total concentration of BIND-014 found in circulation compared to the concentration of encapsulated docetaxel was similar, indicating that the majority of docetaxel likely remains contained within the polymeric particle over the time course evaluated, and that the differentiated PK properties of BIND-014 compared to docetaxel, including greater Cmax and AUC and lower Vd and CL, are likely due largely to retention of encapsulated docetaxel within the vascular compartment. These results are consistent with the favorable tolerability profile of BIND-014 despite the markedly higher plasma concentrations for total BIND-014 compared to docetaxel at similar doses.
Citation Format: Jason M. Summa, Daniel D. Von Hoff, Jasgit C. Sachdev, Monica M. Mita, Patricia M. LoRusso, Peter D. Eisenberg, Howard A. Burris, Lowell L. Hart, Hagop Youssoufian, Donald M. Parsons, Susan C. Low. Evaluation of total and encapsulated drug pharmacokinetics for BIND-014 (docetaxel nanoparticles for injectable suspension) in a phase 1 study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B144.