Population Pharmacokinetics of Trastuzumab-DM1, a First-in-Class HER2 Antibody-Drug Conjugate Given Every 3 Weeks (q3w) and Weekly (qw) to Patients with HER2-Positive Metastatic Breast Cancer (MBC).

Abstract

Abstract BackgroundTrastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody–drug conjugate (ADC) in development for the treatment of HER2-postive MBC. T-DM1 is composed of trastuzumab (Herceptin®), DM1, an inhibitor of tubulin polymerization derived from maytansine, and the stable MCC linker that conjugates DM1 and trastuzumab. T-DM1 has been tested at multiple dose levels in a Phase I trial: q3w (0.3–4.8 mg/kg) and weekly (1.2–2.9 mg/kg), and in two subsequent Phase II trials with T-DM1 administered as a single agent at 3.6 mg/kg q3w. A population pharmacokinetic (PK) model for T-DM1 conjugate was developed using pooled PK data from these trials to estimate typical PK parameter values and inter-patient variability in patients with HER2-positive MBC. The model was further developed to explore and quantify the effect of body size and pathophysiologic covariates on the pharmacokinetics of T-DM1 to better understand the clinical factors that might affect safety for individual patients.MethodsFor the current analysis, 2935 T-DM1 serum concentration–time datapoints from 167 patients were simultaneously fitted using NONMEM® software. T-DM1 concentration-time data to date are best described using a two-compartment linear model. All relevant and plausible covariates likely to have an effect on T-DM1 systemic exposure, e.g., body size covariates (body weight [BW], body surface area [BSA], and body mass index [BMI]), albumin, liver enzymes, creatinine clearance, tumor burden, baseline trastuzumab levels, HER2ECD, concomitant medications, etc., will be explored for possible correlation with the parameters in the model. In addition, the effect of selected covariates on the pharmacokinetics of DM1 is also explored.ResultsEstimated PK parameters for T-DM1 from the base population PK model with data available to date are: clearance (CL) 0.75 L/day, central distribution volume (V1) 3.37 L, peripheral volume (V2) 1.04 L, and inter-compartmental clearance (Q) 0.92 L/day. Inter-individual variability on CL, V1, and V2 was 26%, 17%, and 66%, respectively. Preliminary univariate covariate analysis suggests that body size metric (BSA, WT, BMI) has an influence on exposure of T-DM1. Albumin and tumor burden also appear to influence the clearance of T-DM1. Additional covariate analysis is ongoing. Results of the updated PK model and covariate analysis based on ongoing Phase II trials will be presented at the meeting.ConclusionsModerate inter-individual variability for the estimated PK parameters was observed. The model incorporating all available PK data from Phase I and II trials will help identify clinical factors, from the covariates studied, that affect the pharmacokinetics of T-DM1 and thus potentially, the safety of T-DM1 in individual patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5099.