Abstract 4523: Population pharmacokinetic (PPK) modeling of onapristone in patients (pts) with progesterone receptor (PR)-expressing cancers
Authors: Rezai Keyvan , Cottu Paul , Huguet Samuel , Campone Mario , Italiano Antoine , Varga Andrea , Bonneterre Jacques , Leary Alexandra , Sablin Marie-Paule , Proniuk Stefan , Bexon Alice , Gilles Erard , Bisaha Joseph , Zukiwski Alexander , Lokiec Francois 
Published: August 2015

Abstract
Background: Onapristone is a type I PR antagonist, which prevents PR-induced DNA transcription. Onapristone anti-cancer activity is well documented. An extended-release (ER) tablet formulation of onapristone was designed to address the liver function test (LFT) elevations seen with immediate-release (IR) onapristone. A phase 1 study with onapristone in patients with tumors expressing PR is underway. Objectives included determining the PK profile of ER onapristone using a PPK approach.
Materials and methods: This is an ongoing multi-center, open-label, randomized, parallel-group, 2-stage ph1 study. Female pts ≥18 yrs with tumors expressing PR are eligible. The Stage 1 primary endpoint is the recommended ph2 dose of ER onapristone; secondary endpoints include: safety, efficacy, and PK. Pts received onapristone ER 10, 20, 30, 40 or 50 mg BID, or onapristone IR tablets 100 mg QD until progressive disease or intolerability. PK blood samples from 8 time points were collected over 12 h post-dose Day 1 for the ER and 9 blood samples over 24 h post-dose for the IR formulation. Onapristone plasma concentrations were measured using validated UPLC with tandem mass spectrometry detection (range 1-250 ng/mL). Monolix V4.1 was used to calculate absorption constant (Ka); apparent clearance (CL/F); inter-compartmental clearance (Q); apparent distribution volume (V1/F), 2nd compartment distribution volume (V2) and bioavailability (F) of ER vs IR.
Results: Stage 1 is complete. 42 pts have validated PK data. A 2-compartment open model adequately described the total onapristone time-concentration curve with linear elimination. Results are in Table 1.
Table 1.Estimated PK parameters for onapristone in pts with PR-expressing cancers (n = 42)ParameterValueRelative standard error (%)Ka0.191 h-114CL/F1.51 L/h20Q3.11 L/h25V1/F5.41 L25V241.1 L45F60%20
Conclusions: The PPK modeling described the plasma onapristone time-concentration curves well. A central volume equivalent to the circulating blood volume and a large volume of the deep compartment suggest a large tissue diffusion. PPK/PD modeling to explore safety and efficacy is ongoing, with no overt PK/safety relationship detected.
Citation Format: Keyvan Rezai, Paul Cottu, Samuel Huguet, Mario Campone, Antoine Italiano, Andrea Varga, Jacques Bonneterre, Alexandra Leary, Marie-Paule Sablin, Stefan Proniuk, Alice Bexon, Erard Gilles, Joseph Bisaha, Alexander Zukiwski, Francois Lokiec. Population pharmacokinetic (PPK) modeling of onapristone in patients (pts) with progesterone receptor (PR)-expressing cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4523. doi:10.1158/1538-7445.AM2015-4523