Abstract Background: A novel combination of oral 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. LPT has been shown to be a strong inhibitor of CYP3A4 which is also mainly involved in VNR metabolism. In this study we investigated the potential pharmacokinetic (PK) interactions related to the association of VNR and LPT. 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 orally continuously. Dose levels [DL, LPT (mg)/VNR (mg/m2)] ranged from 750/20 to 1,250/30. A total of 29 patients, 36 to 75 years old, were treated by the association of LPT + VNR. For PK analysis, 7 time point samples were collected on D1 of cycle 1 for LPT and VNR assays. For VNR and LPT respectively, whole blood and plasma concentrations were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modelled using a non linear mixed effect model program (Monolix version 3.1s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: A three-compartment open model adequately described VNR time versus concentration courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance : CL, volume of distribution : V, inter-compartmental clearances : Q) except for Q3 and V3. The population PK parameters obtained for the structural model were: CL=40.2 L/h, V1=8.49 L, Q2=46.9 L/h, V2=1290 L, Q3=61.9 L/h and V3=60.9 L. Influence of platelet counts and LPT dose values on blood VNR CL were significant according to the Bayesian Information Criteria (BIC). A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL=27.9 L/h, V=61.5 L and the absorption constant, ka=0.071 h−1. The ISV were 55.7% and 81.7% for CL and V respectively. No covariate effect, including body surface area and VNR dose values on any PK parameters for LPT could be identified. Conclusions: A PK interaction occured between VNR and LPT. When the LPT dose level increased, the VNR CL decreased significantly, probably due to CYP450-3A4 interaction. The LPT dose which should decrease VNR CL by 50% was defined as 1790 mg. No covariate effects on any LPT PK parameters had been identified. A PK/PD modelling using tumour evaluation and absolute neutrophil count (ANC) is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5468. doi:10.1158/1538-7445.AM2011-5468