Abstract 3780: GEP01: Population pharmacokinetic-pharmacodynamic (PK/PD) model for neutropenia of lapatinib and iv vinorelbine in the treatment of HER2-positive locally advanced or metastatic breast cancer
Authors: Rezaï Keyvan , Urien Saïk , Fumoleau Pierre , Brain Etienne , Roché Henri , Diéras Véronique , Bonneterre Jacques , Jimenez Marta , Lokiec Francois 
Published: August 2012

Abstract
Background: A novel combination of po lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + iv vinorelbine (VNR), a cell-cycle inhibiting agent, could provide a high-potential treatment for locally-advanced or metastatic HER2-overexpressing breast cancer refractory to first or second-line chemotherapy associated to trastuzumab. Neutropenia is the main dose-limiting toxicity occuring in VNR treatment. LPT has been shown to be a strong inhibitor of CYP3A4 which is also mainly involved in VNR metabolism. We have demonstrated a PK interaction related to the combination of VNR and LPT. The aim of this study was to construct a semiphysiological population PK/PD model and to identify PD factors responsible for the neutropenia caused by VNR with this drug combination. Methods: Women with HER2+ locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment, were treated with LPT starting 7 days (D) (D-7 to D0) before adding VNR on a D1 & D8 q3w IV schedule. LPT was given po continuously. Dose levels [DL, LPT (mg)/VNR (mg/m2)] ranged from 750/20 to 1,250/30. For PD analysis, blood count was measured within 7 days before beginning of treatment and up to 3 times per cycle post-treatment. The model consisted of a proliferating compartment that was sensistive to VNR, three transit compartments (transition rate constant, ktr) that represented maturation, and a compartment of circulating blood cells with a feedback mechanism from the circulating cells (Circ0/Circ)α with Circ0 representing the baseline value of circulating neutrophils and a feddback parameter α. VNR concentration-time profiles affected the proliferation of neutrophils by an inhibitory Emax model. Covariate analysis was performed using different patients characteristics and LPT dose level. Population PK/PD was modelled using a non linear mixed effect model program (Monolix version 3.2s). Results: From 29 patients, 552 neutrophil counts were obtained for PK/PD modeling. The mean estimated (SE) parameters obtained for the structural model were CIRC0= 3.7(0.19)*109/L, EC50=0.55(0.01) µg/L, ktr=0.71(0.02) h−1, α=0.24(0.025). No significant covariate effect, including LPT dose values on any PD parameters for VNR could be identified. However, a strong trend was observed between LPT dose level increase and proliferation rate decrease in the proliferating compartments. Conclusions: The model successfully described myelosuppression. When LPT dose increases, ktr value increases and ≤ value decreases indicating a PD interaction between LPT and VNR which is consistent with PK interaction observed between these two drugs. This PK/PD interaction might increase the exposure to VNR and consequently alter the hematological tolerance. A predictive PK/PD modeling of tumor growth kinetics in patients is ongoing.
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 3780. doi:1538-7445.AM2012-3780