Abstract 31: A population pharmacokinetic-pharmacodynamic (POP-PK/PD) modelling of EZN-3042 administered with or without docetaxel in patients with advanced solid tumors or lymphoma.
Authors: Baudry E , Rezai Keyvan , Urien Saik , Tolcher Anthony , Patnaik Amita , Papadopoulos Kyriakos P. , Agnew James , Buchbinder Aby , Lokiec Francois 
Published: August 2014

Background: Survivin, a member of the apoptosis protein inhibitor family, is an essential regulator of cell division and a modulator of programmed cell death. Overexpression of survivin has been noted in multiple cancers and is associated with poor prognosis and decreased overall survival.

The survivin mRNA antagonist EZN-3042 is a locked nucleic acid (LNA)-antisense oligonucleotide (ASO) that specifically down-modulates survivin mRNA and consequently protein.

The objectives of this study are to determine the recommended dose, pharmacokinetics (PK), and pharmacodynamics (PD) and to perform a POP-PK/PD modeling of EZN3042 in patients with advanced solid tumors or lymphoma.

Materials and Methods: A phase 1, open-label, dose-escalation study evaluating the safety and tolerability of EZN-3042 given weekly as a 2-hour iv infusion was previously presented (AACR; San Francisco, CA; November 13, 2011). Dose levels ranged from 2.5 mg/Kg to 8.0 mg/Kg. For PK analysis, 10 time point blood samples were collected on D1 of cycle 1 and 1 blood sample just before administration (Cmin) was collected on D1 of each subsequent treatment cycle.

POP-PK/PD analyses were carried out using the nonlinear mixed effect modeling software program Monolix version 4.1.2. Proportional residual variability and exponential between subject variabilities (BSVs) were used. Different covariates including Body Weight (BW), and sex were investigated. The PK parameters were allometrically normalized for BW to a 70 kg individual.

Results: From 30 patients (16 males, 14 females), 479 time-plasma concentrations and 307 ANC were available for analysis. A 3-compartment open model adequately described the total EZN3042 time-concentration curve with linear elimination. The BSVs could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, inter-compartmental clearances: Q) except for V2 and V3.

The main PK parameters (RSE%) estimated for EZN3042 were CL=4.2 (17%) L/h, Q2=0.26 (31%) L/h, Q3=1.22 (13%) L/h, V1=11.7 (6%) L, V2=3.7 (17%) L, and V3=640 (10%) L.

The main covariate effects were related to BW, only V1 (central volume) was influenced by BW.

Conclusions: The POP-PK modeling satisfactorily described the plasma EZN-3042 time-concentration curves in patients. The main covariate effect was related to BW and this influenced only the central volume of distribution. This indicates that the central volume of distribution of EZN-3042 increased when the body weight increased. A central volume higher than the circulating blood volume and a large volume of the deep compartment suggest that EZN-3042 has large tissue diffusion. POP-PK/PD modeling with ANC is ongoing.

Citation Format: E Baudry, Keyvan Rezai, Saik Urien, Anthony Tolcher, Amita Patnaik, Kyriakos P. Papadopoulos, James Agnew, Aby Buchbinder, Francois Lokiec. A population pharmacokinetic-pharmacodynamic (POP-PK/PD) modelling of EZN-3042 administered with or without docetaxel in patients with advanced solid tumors or lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 31. doi:10.1158/1538-7445.AM2013-31