Abstract 3792: Population Pharmacokinetic (PPK) modeling of ProLindac™ (AP5346), a nanopolymer prodrug of diaminocyclohexane (DACH)-platinum (Pt) in recurrent advanced ovarian cancer (AOC) patients

Background: ProLindac™ (PL) is a 25 kDa hydroxypropylmethacrylamide copolymer linked to a DACH-Pt. The DACH-Pt complex is thought to be biologically inert while attached to the polymer, with slow in vivo Pt release accelerated in low pH environments (extracellular space of hypoxic tumor and intracellular lysosomal compartment). Methods: 9/35 patients (pts) with recurrent OAC treated with single-agent PL via 2-h IV infusion at doses of 900 mg/m*2 q2w (3 pts), 1400 mg/m*2 q3w (3 pts) and 1680 mg/m*2 q3w (3 pts) were assessable for full PK analysis. 8 time point samples were collected on cycle 1, and 2 samples at cycles 2, 3 and 4. The ultrafiltration procedure used Ultra-4 filters (Amicon) with 50 kDa for unbound PL (U-PL) and 3 kDa for unbound Pt (U-Pt) cut-off. Urine was collected every 6 h from day 1 to 5 of dosing 1. Pt levels were measured by a validated Flameless Atomic Absorption Spectrometry Method (concentration range: 12.5 - 500 ng/mL). PPK was modeled using a nonlinear mixed effect model program (Monolix version 3.1s) by computing the maximum likelihood estimation of the parameters without any approximation of the model. Results: A 3-compartment open model adequately described the total PL time-concentration curve with linear elimination while a 2-compartment model satisfactorily described U-PL and U-Pt time-concentration curves with linear elimination. Mean PPK parameters with SD are summarized below: The mean recovery of PL dose in urine was at least 60% within 5 days. Conclusion: The central Vd for total PL Pt is rather small, close to the circulating blood volume suggesting that the major part of parent drug is restrained in the circulatory space with weak tissue diffusion probably due to a high protein binding rate. However, for U-PL and U-Pt, the Vd is much higher suggesting: 1) a significant tissue diffusion of active species (free-Pt), 2) PL is bound to plasma proteins with low-energy bonds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3792. doi:1538-7445.AM2012-3792