Physiologically based, POP-PK modelling of Strontium Ranelate in the ovariectomised rat disease model of post menopausal osteoporosis.
H. Pertinez, L. Aarons
University of Manchester
Objectives: Strontium is a bone seeking agent currently prescribed for the treatment of post menopausal osteoporosis. The aim of the work described in this poster was to develop a physiologically based pharmacokinetic (PBPK) model that would be able to describe bone exposure data for Strontium in the ovariectomised (OVX) rat pre-clinical disease model for post menopausal osteoporosis. The PBPK model would then serve as the basis for a human PBPK model for Strontium in future work, through the application of standard scaling methodologies.
Methods: For initial PBPK model development a na´ve pooled approach was taken with the data and nonlinear regression used for parameter optimization. Once a suitable model was developed, a more appropriate POP-PK approach (given the nature of the OVX rat exposure dataset) could then be taken. The final PBPK model design incorporated elements from literature PBPK models for bone seeking agents áallowing for a description of the heterogeneity of bone tissue in the structure of the model (i.e. cortical and trabecular bone compartments and bone surface and bone matrix sub-compartments) and also for a physiologically rationalized description of the processes of bone remodelling. Descriptions of tissues other than bone adopted standard perfusion rate limited tissue compartment models, making use of a separate rat tissue distribution study for Strontium to provide required tissue Kp values. The model was implemented in both open loop and closed loop configurations. For the former, a forcing function for the blood/plasma compartment was derived from an empirical, 3-compartment , 1st order absorption model, POP-PK fitting to the OVX rat plasma exposure data (in a combined analysis with a satellite IV rat PK study), carried out in a Bayesian paradigm in WinBUGS using non-informative priors. Once adequate performance of the PBPK model had been demonstratedá in open and closed loop configurations, treating the data with a na´ve pooled approach, the bone exposure data was re-analysed with the PBPK model in an open loop configuration, using a Bayesian POP-PK approach in WinBUGS. In this analysis individual PK parameter estimates from the empirical fit to plasma data were used to provide a subject specific forcing function for each individual in the bone dataset.
Results and Conclusions: The PBPK model successfully describes the bone exposure of Strontium in the OVX rat in a physiologically rationalized manner. Parameter estimates and model behaviour are in keeping with known aspects of the distribution and incorporation of Strontium into bone and the model has the potential for future use in modelling the PK-PD of Strontium and/or other bone seeking agents and for scaling to model human bone exposures for Strontium.
. Stepensky, D., L. Kleinberg, and A. Hoffman, Bone as an effect compartment : models for uptake and release of drugs. Clin Pharmacokinet, 2003. 42(10): p. 863-81.