Integrated cellular bone homeostasis model for denosumab pharmacodynamics in multiple myeloma patients

Abstract

The purpose of this study is to integrate a cellular bone homeostasis model with the pharmacokinetics (PK) of denosumab, an inhibitor of receptor activator of nuclear factor‐κB ligand, to characterize the time course of serum N‐telopeptide (NTX), a bone resorption biomarker, following single escalating doses in multiple myeloma (MM) patients. Mean PK and serum NTX temporal profiles were extracted from the literature. Nonlinear denosumab PK profiles were well described by a model that includes rapid binding of the drug to its pharmacological target. These PK profiles were integrated into a previously reported theoretical cellular model of osteoblast‐osteoclast interactions. Serum NTX concentrations were linked to a resorbing active osteoclast (AOC) pool by a nonlinear transfer function. Reasonable fits were obtained for the NTX profiles from maximum likelihood estimation using the final model. Transfer function parameters, including the basal NTX level independent of AOC and the AOC concentration producing 50% of maximal NTX production, were estimated with good precision as 5.7nM and 1.2x10−5pM. In summary, an integrated cellular model was developed to quantitatively describe clinical biomarker data and may also provide a means for testing hypotheses on the role of cellular system variables in controlling drug response. This study was funded by Grant GM57980 and a postdoctoral fellowship from Amgen, Inc.