A physiologically based pharmacokinetic model for strontium exposure in rat

摘要

Purpose: To develop a physiologically based pharmacokinetic (PBPK) model to describe the disposition of Strontium - a bone seeking agent approved in 2004 (as its Ranelate salt) for treatment of osteoporosis in post-menopausal women. Methods: The model was developed using plasma and bone exposure data obtained from ovariectomised (OVX) female rats - a preclinical model for post-menopausal osteoporosis. The final PBPK model incorporated elements from literature models for bone seeking agents allowing for description of the heterogeneity of bone tissue and also for a physiological description of bone remodelling processes. The model was implemented in MATLAB in open and closed loop configurations, and fittings of the model to exposure data to estimate certain model parameters were carried out using nonlinear regression, treating data with a na?ve-pooled approach. Results: The PBPK model successfully described plasma and bone exposure of Strontium in OVX rats with parameter estimates and model behaviour in keeping with known aspects of the distribution and incorporation of Strontium into bone. Conclusions: The model describes Strontium exposure in a physiologically rationalized manner and has the potential for future uses in modelling the PK-PD of Strontium, and/or other bone seeking agents, and for scaling to model human Strontium bone exposure.