Pharmacokinetic (PK) Interactions between Lapatinib (L) and Vinorelbine (VNR) in a Phase I Study in Locally Advanced or Metastatic Breast Cancer (LAMBC) Patients(Pts) Overexpressing HER2. GEP-01 – A Study of the FNCLCC-Group of Early Phase Trials.

Abstract

Abstract Background: Lapatinib is effective in overexpressing HER2 LAMBC pts. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Both drugs use the same main metabolic pathway: Cytochrome P450 3A4. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies, and looking for the PK interactions between the 2 drugs.Methods: Women with HER2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7 day (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w iv regimen. L was given po continuously. G-CSF as primary prophylaxis of febrile neutropenia (FN) was not permitted. Dose levels (DL) (L mg/VNR mg/m²) ranged from 750/20 to 1250/30 with 3 patients per DL. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. PK time points analysis was performed on plasma for L and whole blood for VNR. For both drugs the analytical method was Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry (MS-MS) as detection. VNR PK parameters were estimated by nonlinear mixed effect modeling (NONMEM) and L PK parameters were estimated by non compartmental software (MicroPharm).Results: Seventeen pts and 68 PK time points were available for VNR analysis. VNR was ascribed to a tri-compartment model. When considering all VNR data together, VNR clearance (CL) was 37.8±16.7 L/h, while it showed a gradual decrease according to specific dose of L: 47.5±20.4 L/h for L 750 mg (3 patients) vs 35.6±4.3 L/h for pooled data for L 1000 and 1250 (14 patients). This trend was not significant likely due to low number of patients treated at lower dose of L, while no significant difference was observed between L 1000 and L 1250. The mean elimination half life time (t1/2) of VNR was 0.12 h. Six patients and 42 PK time points were analyzed for L. L CL were respectively 83.8 ± 41.3 and 57.1 ± 5.5 L/h for patients who received 750 mg (3 patients) and 1000 mg (3 patients) of L with 20 mg of VNR. The mean elimination half life time (t1/2) of L was 2.89 h.Conclusions: A potential PK interference occurred between VNR and L. When the dose of L increased, both VNR and L CL decreased, likely due to CYP450-3A4 interactions. This trend should be confirmed by the PK analysis of L and VNR in more patients, including an intermediate DL (1250/22.5) still ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5091.