Integrated Cellular Bone Homeostasis Model for Denosumab Pharmacodynamics in Multiple Myeloma Patients

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Abstract
The purpose of this study is to couple a cellular bone homeostasis model with the pharmacokinetics (PK) and mechanism of action 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 median serum NTX temporal profiles were extracted from a previously conducted randomized, double-blind, double-dummy, active-controlled, multicenter study including 25 MM patients receiving escalating denosumab doses. Nonlinear denosumab PK profiles were well described by a target-mediated disposition model that includes rapid binding of drug to its pharmacological target. Fixed PK profiles were integrated into a previously reported theoretical cellular model of osteoblast-osteoclast interactions, and the 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 maximal likelihood estimation using the final model. Transfer function parameters, including the basal NTX level and the AOC concentration producing 50% of maximal NTX production, were estimated with good precision as 5.55 nM and 1.88 × 10–5 pM. An indirect response model for inhibition of NTX production by denosumab was also used to characterize the data. Although this model adequately characterized the pharmacodynamic data, simulations conducted with the full model reveal that a cellular model coupled with clinical data has the distinct advantage of not only quantitatively describing data but also providing new testable hypotheses on the role of cellular system variables on drug response.