Comment from William Zamboni

From William C. Zamboni, PharmD, PhD - Director, Cancer Pharmacokinetics and Pharmacodynamics Facility; Co-Leader, Immunology and Drug Development Center; UPMC Hillman Cancer Center; Pittsburgh, PA; Email: zamboniw@upmc.edu. I have been involved in translational development and pharmacology studies of complex drugs (e.g., nanoparticles, conjugates, and biologics) for >25 years. Unlike standard small molecule drugs, complex drugs are cleared via cells (e.g., monocytes and macrophages) of the innate immune system (IIS). For example, biologics such as antibodies and antibody drug conjugates (ADC) are cleared via Fc-gamma-receptors (FcRs) on IIS cells. Variability in the ability of IIS cells to take up antibodies and ADCs impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of these agents. Studies suggest that differences in body size and body habitus (i.e., composition of the body) affect the function of the IIS. However, the interaction between body size and habitus and the IIS may be disease or cancer specific. In general, an increase in body size as measured by total body weight (TBW) and/or increase in IIS is associated with increased clearance and lower exposure of biologics and potentially lower response. This occurs even with weight-based dosing (mg/kg) and especially flat dosing (mg) of biologics. With weight-based or flat tiered dosing (separate low and high doses based on body size), the patients with the highest risk of under-dosing are patients with TBW near the upper limit of the lower dose cohort or obese patients. In addition, this issue occurs as patients increase in size (e.g., pediatric patients grow) or body composition changes (e.g., on weight loss drugs). Thus, additional studies are needed to optimize the dose of complex drugs, especially biologics, in special cohorts and populations. In addition, studies are needed to develop novel metrics of body size and body habitus, and biomarkers of the IIS to optimize the dose of these agents.