Abstract 2049: Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel
Authors: Rezai Keyvan , Huguet Samuel , Madar Olivier , Extra Jean-Marc , Provansal Magali , Tarpin Carole , Isambert Nicolas , Pakradouni Jihane , Goncalves Anthony , Lokiec François 
Published: July 2016

Introduction: LY2780301 is an orally available small molecule dual inhibitor of p70 S6 kinase and AKT. LY2780301 is an inhibitor of CYP3A4. By the one hand, Paclitaxel (PXL) undergoes extensive metabolism via CYP450 2C8 and CYP450 3A4 pathways. By the other hand, PXL induces weakly CYP3A4 activity. In this study we investigated for the first time, the potential pharmacokinetic (PK) drug-drug interaction (DDI) related to the combination of both drugs LY2780301 and PXL.

Methods: Women with HER2- locally advanced or metastatic breast cancer, with and without PI3/AKT pathway activation, were treated with weekly administration of PXL on day1 (D1), D8 and D15. LY2780301 was administered by a daily flat dosing regimen starting at D3. Dose levels [DL, LY2780301 (mg/day)/PXL (mg/m2/week)] ranged from 400/70 to 500/80. For PK analysis, 7 time point samples were collected on D1 and D3 of cycle 1 for PXL and LY2780301 respectively. 7 samples were collected on D8 for both drugs. LY2780301 plasma concentrations were measured using Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry validated method. PXL plasma concentrations were measured using UPLC coupled with UV validated method. A joint population PK (PK-POP) model has been developed for LY2780301 and

its main metabolite. PK-POP modelling has been performed with a non linear mixed effect model program (Monolix version 4.3.2).

Results: 12 patients, 35 to 67 years old, were treated. A total of 160 and 157 concentrations for LY2780301 and its metabolite were used respectively for PK-POP modeling. A one compartment open model adequately described LY2780301 and its metabolite concentration versus time courses respectively with the estimation of the fraction of absorbed dose (fm) of LY2780301 metabolised in that metabolite. The interindividual variabilities (ISV) could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, L and the absorption constant: Ka). The population PK parameters obtained for the structural model were: Ka = 0.536 h−1, CL/F = 3.57 L/h, V/F = 85.2 L, CL/(F*fm) = 13.2 L/h, V2/(F*fm) = 13.2 L, fm = 0.747 for LY2780301 and its metabolite respectively. PXL increases LY2780301 CL from 3.57 to 4.4 L/h (p = 0.016).

Conclusions: We have demonstrated a PK DDI between LY2780301 and PXL. PXL increases LY2780301 CL and decreases LY2780301 AUC. PXL PK modeling is ongoing in order to verify the effect of LY2780301 on PXL PK.

Citation Format: Keyvan Rezai, Samuel Huguet, Olivier Madar, Jean-Marc Extra, Magali Provansal, Carole Tarpin, Nicolas Isambert, Jihane Pakradouni, Anthony Goncalves, François Lokiec. Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2049.