Chapter 6 - Denosumab: dosing and drug interaction challenges on the path to approval

Abstract

Denosumab is a monoclonal antibody to the Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL), which is critical for osteoclast maturation and activity, and is approved in multiple indications, including the treatment of post-menopausal osteoporosis and to reduce the risk of skeletal related events in advanced cancer patients. During its development, it became apparent that markedly different dosing regimens were appropriate in the distinct patient populations and given the differences in the intent of treatment. Justifying the dose regimens used in the pivotal clinical trials, before and after their conduct (in the Biologics Licensing Application; BLA), varied from a relatively straightforward but sound empirical approach to a rationale underpinned by pharmacometrics and clinical trial simulations. RANKL is classified as a cytokine, and around the time of the initial BLA, there was increasing awareness of potential disease-drug interactions, in which a cytokine reduces cytochrome P450 enzyme (CYP) activity that is then “normalized” by an inhibitory biologic, resulting in lower exposures of a concomitant substrate of the CYP. This chapter summarizes the dose rationales that supported denosumab development and approval, as well as the arguments put forth during BLA review on its disease-drug interaction potential, and the outcomes of these regulatory interactions.