PK-PD modelling of bone density and turnover effects of denosumab based on a circular model of bone remodelling
Erno van Schaick (1), Philippe Jacqmin (1), Juan Jose Perez-Ruixo (2), Jenny Zheng (2)
(1) Exprimo N.V., Mechelen, Belgium (2) PKDM, Amgen Inc, Thousand Oaks, USA
Objectives: To evaluate and update a previously developed bone cycle model (BCM) to describe the long-term effects of denosumab on bone density and bone turnover.
Methods: Bone turnover markers and bone mineral density (BMD) changes following treatment with denosumab, a fully human monoclonal antibody to RANK ligand (RANKL), were modelled using the BCM. The data were from a phase 2 trial in postmenopausal women, where denosumab was given every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg) for 24 months followed by either a continued treatment of 60 mg Q6M, off treatment for 24 months, or an off treatment for 12 months followed by re-initiation of 60 mg Q6M denosumab for 12 months . Individual predicted denosumab concentrations obtained from the population pharmacokinetic analysis, serum C-telopeptide (sCTX), bone specific alkaline phosphatase (BSAP) and BMD were jointly modelled using NONMEM.
Results: A mechanism based circular multi-compartmental model with distinct compartments representing bone remodelling (bone resorption, collagen matrix formation, and fast and slow mineralization) was used. Disease progression, rebound of sCTX, BSAP and BMD upon termination of denosumab, and inhibitory effect of denosumab on resorption were estimated. Some parameters describing the bone remodelling process were derived from literature or previous analyses. The model satisfactory described biomarker-time profiles after denosumab long-term treatment, but underestimated the rebound in sCTX and BSAP upon termination of treatment. Predictive checks indicated that the model adequately predicted changes in BMD. External validation of the model is currently ongoing.
Conclusions: The adapted bone cycle model adequately described the changes in bone turnover markers and BMD following treatment of denosumab at different doses and dose schedules. Improvement may still be envisaged, but may need a more mechanistic description of denosumab’s action on osteoclast activity.
Acknowledgement: The initial structural development of the bone cycle model was performed by Exprimo in collaboration with F.Hoffmann-La Roche Ltd.
 Miller et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial. 2008 Bone 43: 222-229.