Clinical development of subcutaneous dosing alternatives to established intravenous formulations for monoclonal antibodies—pharmacokinetic-based bridging approach

Subcutaneous dosing alternatives for high-dose monoclonal antibodies (mAbs) are increasingly developed in oncology and patient and healthcare providers broadly prefer subcutaneous injections over more invasive intravenous infusions. The inherently reduced dosing complexity due to the broad application of subcutaneous fixed-dose regimens and the feasibility of a fast bolus injection contributes to a reduction in time a patient spends in the hospital and frees up resources in the healthcare institution. When developing the first high-volume subcutaneous formulation in the field, clinical requirements for drug delivery alterations for small molecules did serve as a precedent. Here, the development of novel oral formulations for established small molecule drugs with the aim to reduce the number of pills that need to be taken per day is tightly regulated. In case the novel formulation technology changes the pharmacokinetic profile of the molecule, manufacturers need to demonstrate that these changes do not impact the established efficacy and safety profile of the molecule. Depending on the available pharmacokinetic–pharmacodynamic correlation for the respective small molecule, development programs span from demonstration pharmacokinetic comparability to the generation of supporting efficacy and safety data. In analogy to these small molecule programs, changing from intravenous to subcutaneous administration for a given mAb while maintaining the dosing frequency and overall exposure results in a lower maximum serum concentration (Cmax) and a delayed corresponding time to reach Cmax (tmax). Subcutaneous development programs therefore typically consist of a pharmacokinetic-based dose finding and a phase 3 noninferiority trial to generate supporting efficacy and safety data. In these studies, a pharmacokinetic parameter [i.e., serum trough concentrations (Ctrough) and/or the area under the serum concentration–time curve] can be the primary or coprimary endpoint. Different to small molecules, immunogenicity is a crucial part of the overall development program. Clinical trials are designed to demonstrate that the changed absorption pathway of a mAb following subcutaneous administration, that is, occurring predominantly via the lymphatics, does not result in an increase in clinically relevant antidrug antibodies as compared to intravenous infusion directly into the systemic circulation. While the option to administer high-dose mAbs subcutaneously has already reduced costs and resources associated with parenteral drug administration in a controlled healthcare setting, the next step in the process toward patient-centric product presentations would be the availability of automated high-volume wearable on-body delivery systems that may facilitate home- or even self-administration for eligible molecules and patients.