Trastuzumab, development

Standardization of IHC/ICC has been a critical issue for more than three decades, especially with the advances in targeted therapy such as the development of trastuzumab (Herceptin) for advanced breast cancer.51 Nevertheless, standardization is a difficult issue because numerous factors may influence the consistency and reliability of immunostaining results, including fixatives, fixation time, AR, antibody clones, detection system, and interpretation (see Part II). In cytopathology, the situation is even worse due to its variable cell sample preparation techniques. Cytopreparation is. .. the foundation of cytomorphology. 52 We believe it is also the foundation of ICC. Therefore, standardization of ICC needs to start with uniform and reliable cytopreparation. 

An assumption concerning the number of compartments is, by nature, not required. For reliable results and precise parameter estimates, however, a relatively large number of data points per individual are required. Phase 1 studies of mAbs usually provide sufficient data for a noncompartmental analysis, but the assumption of linear pharmacokinetics is not valid for most mAbs. This prerequisite, however, was frequently neglected during the early years of therapeutic mAh development, and an overall estimate for CL, for example, was frequently reported in the literature. In dose-escalating studies, however, the concentration-time plots of the raw data clearly indicate that the slope of the terminal phase is not parallel for the different doses, but increases with increasing dose (Fig. 3.10). As a result, the listing of different clearance values for different doses can be found. For example, the clearance of trastuzumab was reported to be 88.3 mL/h for a 10-mg dose, 34.3 mL/h for a 50-mg dose, 25.0 mL/h for a 100-mg dose, 19.0 mL/h for a 250-mg dose, and 16.7 mL/h for a 300-mg dose. 

Various methods are available to estimate population parameters, but today the nonlinear mixed effects modeling approach is the most common one employed. Population analyses have been performed for mAbs such as basiliximab, daclizu-mab and trastuzumab, as well as several others in development, including clenolixi-mab and sibrotuzumab. Population pharmacokinetic models comprise three submodels the structural the statistical and covariate submodels (Fig. 3.13). Their development and impact for mAbs will be discussed in the following section. 

Controversy exists as to the most useful assay for HER2-overexpres-sion, particularly for identification of candidates for trastuzumab therapy. Following the approval of trastuzumab, an IHC-based assay (Herceptest), similar but not identical to the trastuzumab clinical trials assay, was developed for this use. Fluorescence in situ hybridization (FISH)-based assays have also been developed to determine HER2 gene amplification. The concordance of these assays with each other and with the trastuzumab clinical trials assay has been questioned (252). Since the probability of response to trastuzumab therapy appears to correlate with the level of HER2 overexpression, further studies will be required to establish standardized HER2 testing procedures. 

Personal communications from Rob Dies (sildenafil, Viagra ), Jianguo Li (zanamivir, Relenza ), Mike Staschen (trastuzumab, tier cep tin ), Theo Jang (rofecoxib, Vioxx ), and Agnes Westelinck (etanercept, Enbrel ), Center for Drug Development Science, University of California, San Francisco, Washington, D.C. 

An overweight 59-year-old woman with hypertension and asthma developed breast cancer (ER-I-/PR-I-/ HER2-2-I-) (3). Her MUGA scan showed a left ventricular ejection fraction of 57%. She was given trastuzumab with docetaxel and had a good response after 4 months. Before surgery she became dyspneic, and a... 

Trastuzumab also may cause infusion-related or hypersensitivity reactions (particularly with the first infusion). However, a more concerning possible side effect is cardiac dysfunction (including CHF). Although patients may develop cardiac dysfunction with trastuzumab alone, the incidence is significantly increased in patients who receive trastuzumab in combination with paclitaxel or in those patients with previous use of anthracyclines. 

Trastuzumab-DMl/ Herceptin-DMl a-Her2/neu-DMl TAP (humanized by CDR grafting and framework changes) Breast Genentech" Preclinical development 38... 

Harries M, Smith I, The development and clinical use of trastuzumab (Herceptin), Endocr Relat... 

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