Abstract B191: Phase 1 pharmacokinetic (PK) assessments of ATI-1123, a novel human serum albumin-stabilized nanoparticle docetaxel liposomal formulation, in patients with advanced solid malignancies.
Authors: Mahalingam Devalingam , Mita Alain , Kousba Ahmed , Vemulapalli Sushma , Gallegos Nicole , Anderson Gavin , Charles J. , Rogers Jon M. , Sarantopoulos John , Mita Monica , Senzer Neil , Nemunaitis John 
Published: June 2012

Abstract
Purpose: ATI-1123, a novel nanoparticle docetaxel liposomal formulation, is being investigated in patients (pts) with advanced solid malignancies. ATI-1123 is expected to reduce hypersensitivity reactions, have a broader therapeutic index and to enhance systemic exposure docetaxel. The objective of this study was to investigate the safety, tolerability, pharmacokinetics and tumor response of ATI-1123 in pts with advanced solid tumors following escalating doses of intravenously administered ATI-1123.
Methods: This phase I study enrolled 29 pts. The dosing (1 hr infusion q 3 weeks) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. ATI-1123 doses ranged from 15 to 110 mg mg/m2. Plasma samples were obtained at baseline, 0.25, 0.5, 1, 2, 4, 8–10, 24, 48 hrs, day 8, and analyzed for encapsulated and non-encapsulated docetaxel using a validated HPLC MS/MS (BQL &lt; 0.405 and 0.595 ng/mL, respectively). PK parameters were determined for encapsulated, the non-encapsulated and total docetaxel in each subject by standard model independent methods (Gibaldi and Perrier, 1982) using WinNonlin Professional 5.2.1 (Pharsight Corp., Mountain View, CA). Dose proportionality for the three analytes was assessed using a power-law model, linear-regression model and ANOVA model.
Results: Total docetaxel Cmax, AUC(0-inf), T1/2, CL, and Vss mean values ranged from 2060 × 643 to 16200 × 2310 ng/mL, 5710 × 1550 to 40400 × 6160 ng·h/mL, 6.57 × 0.555 to 7.32 × 0.958 h, 2.63 × 0.741 to 3.43 × 1.50 L/h/m2 and 13.3 × 2.06 to 17.1 × 10.4 L/m2, respectively. Corresponding values for encapsulated docetaxel were 1560 × 460 to 9890 × 2170 ng/mL, 4480 × 1380 to 28500 × 7040 ng·h/mL, 5.08 × 1.08 to 6.23 × 0.732 h, 3.51 × 1.08 to 4.42 × 1.09 L/h/m2 and 15.0 × 3.11 to 21.3 × 3.68 L/m2. Encapsulated docetaxel Cmax and AUC were up to 4-fold higher while clearance were up to 4-fold lower than the corresponding values for non-encapsulated docetaxel (free portion). T1/2 values were ∼2–3-fold lower. The PK parameters for free docetaxel are in reasonable agreements with the values reported in the literature for standard docetaxel (Stephen et al., 1999, Bruno et al., 1998, Bruno et al., 1997). The PK exposure of encapsulated, non-encapsulated and total docetaxel was dose proportional as determined by the power-law model where the slope of Ln Cmax or Ln AUC vs. Ln dose has value of ∼1 and 90% confidence intervals for the slope include 1. In addition, p values determined by regressions models and ANOVA for slope and intercepts of Cmax or AUC (or normalized Cmax and AUC) vs. dose supported dose proportionality.
Conclusions: ATI-1123 exhibited favorable PK in humans and the presence of the encapsulated docetaxel lead to the enhanced exposure of docetaxel. The PK exposure of encapsulated, non-encapsulated and total docetaxel was dose proportional. The estimated PK parameters for non-encapsulated docetaxel (free portion) are in reasonable agreements with the corresponding values reported in the literature for standard docetaxel.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B191.