Physiologically based modelling of the pharmacokinetics of Strontium Ranelate, as used in the treatment of Osteoporosis.

Abstract

Osteoporosis is a common disease of the bone characterized by a reduction inbone mineral density and associated deterioration of bone tissue, leading toincreased bone fragility and susceptibility to fractures. It is of rising prevalencein the developed world, particularly among postmenopausal women, aspopulations become increasingly elderly. Strontium, administered orally as itsRanelate salt, has been identified and developed as a treatment for osteoporosisthat shows both anti-resorption and pro bone-formation effects in bone tissue.The aim of this thesis was to apply physiologically based pharmacokinetic(PBPK) techniques to the modelling of Strontium exposure data, derived fromstudies where its application as a treatment for osteoporosis was beinginvestigated. It is hoped this work will be able to contribute to the understandingof Strontium's physiological disposition and mechanism of action in treatmentof osteoporosis, and also potentially be applicable to the pharmacokineticmodelling of other bone seeking agents. Due to the nature of the data availablewith which to construct the model, work would focus on developing a PBPKmodel in the rat, used as a preclinical test species for Strontium, before scalingthis model to human.Empirical nonlinear mixed effects modelling was undertaken of available ratand human plasma data which had matching bone exposure data, to provideforcing functions for open loop configuration PBPK modelling of Strontium.Parameter estimation adopted a Bayesian approach in WinBUGS. In the rat a 3-compartment empirical model was fitted to the available plasma data usinguninformative Bayesian priors. In human, informative Bayesian priors wereused to propagate information from earlier phase clinical trial studies with richlysampled shorter timecourses, to fit a 4-compartment empirical model to phase IIclinical trial plasma data with sparse sampling and a much longer timecourse.Evidence was also found to show that the oral exposure of Strontium may benonlinear with dose.A PBPK model for Strontium was developed based on an implementation of theO'Flaherty PBPK model for Lead. Two model versions were produced, the firstwith a direct implementation of the O'Flaherty Lead model compartmentalstructure. The second, a reduced version combining mechanistic descriptions ofbone disposition processes in the O'Flaherty model with a simplercompartmental structure. Both versions successfully describe rat bone exposurein open and closed loop configurations, and the reduced version was usedsuccessfully to estimate rat PBPK parameters in a Bayesian mixed effectsparadigm and also to predict human bone exposure after appropriate scaling ofthe model parameters.

Date of Award	1 Aug 2011
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Leon Aarons (Supervisor)