Fixed Dosing of Monoclonal Antibodies in Oncology

Abstract

Most monoclonal antibodies in oncology are administered in body-size-based dosing schedules. This is believed to correct for variability in both drug distribution and elimination between patients. However, monoclonal antibodies typically distribute to the blood plasma and extracellular fluids only, which increase less than proportionally with the increase in body weight. Elimination takes place via proteolytic catabolism, a nonspecific immunoglobulin G elimination pathway, and intracellular degradation after binding to the target. The latter is the primary route of elimination and is related to target expression levels rather than body size. Taken together, the minor effects of body size on distribution and elimination of monoclonal antibodies and their usually wide therapeutic window do not support body-size-based dosing. We evaluated effects of body weight on volume of distribution and clearance of monoclonal antibodies in oncology and show that a fixed dose for most of these drugs is justified based on pharmacokinetics. A survey of the savings after fixed dosing of monoclonal antibodies at our hospital showed that fixed dosing can reduce costs of health care, especially when pooling of preparations is not possible (which is often the case in smaller hospitals). In conclusion, based on pharmacokinetic parameters of monoclonal antibodies, there is a rationale for fixed dosing of these drugs in oncology. Therefore, we believe that fixed dosing is justified and can improve efficiency of the compounding. Moreover, drug spillage can be reduced and medication errors may become less likely.

Implications for practice: The currently available knowledge of elimination of monoclonal antibodies combined with the publicly available data from clinical trials and extensive population pharmacokinetic (PopPK) modeling justifies fixed dosing. Interpatient variation in exposure is comparable after body weight and fixed dosing and most monoclonal antibodies show relatively flat dose-response relationships. For monoclonal antibodies, this results in wide therapeutic windows and no reduced clinical efficacy after fixed dosing. Therefore, we believe that fixed dosing at a well-selected dose can increase medication safety and help in reduction of costs of health care without the loss of efficacy or safety margins.

Keywords: Cancer; Fixed dosing; Monoclonal antibodies.

Figure 1.

Metabolism of monoclonal antibodies. Antibodies are metabolized via proteolytic catabolism (A) and intracellular degradation after binding to the target (B). Proteolytic catabolism takes place in cells after endocytosis of the antibody. In this process, the antibody is engulfed by the cell membrane (A1) and catabolized by lysosomes (A2) inside the cell. In the absence of the neonatal Fc receptor (FcRn, or Brambell receptor), this would lead to rapid clearance of monoclonal antibodies (A3a). However, this receptor is expressed in vascular endothelium, immune cells (e.g., macrophages and dendritic cells), intestinal epithelium, and hepatocytes and binds to monoclonal antibodies (A3b). After binding, the FcRn receptor mediates monoclonal antibody transport to the extracellular matrix, thus preventing intracellular breakdown by catabolism (A4). A second, more rapid elimination route for many monoclonal antibodies is target binding (B1). This is followed by internalization of the monoclonal antibody‐target complex (B2) and intracellular degradation (B3). Characteristics of both elimination routes are presented in Table 2.