Abstract
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 naïve-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.
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Abbreviations
- Art-blood:
-
Arterial Blood
- Ax :
-
Amount of Strontium in tissue compartment x (mg)
- BFR:
-
Total Bone Formation rate (L/h)
- Clx :
-
Clearance of Strontium from blood by compartment x (L/h)
- Cx :
-
Concentration of Strontium in tissue compartment x (mg/L) equal to Ax/Vx
- FBFR:
-
Fractional Bone Formation Rate
- Fu :
-
Fraction unbound of Strontium in blood
- ka:
-
1st order absorption rate constant for Strontium from gut depot into gut tissue (h−1)
- Kp−x :
-
Tissue to blood partition coefficient for tissue compartment x
- PP:
-
Poorly perfused tissues
- Qx :
-
Blood flow to tissue compartment x (L/h)
- STRONT:
-
Dimensionless scaling factor for Intercompartmental clearance of Strontium from bone tissue surface to bone tissue matrix
- Ven-blood:
-
Mixed Venous blood
- Vx :
-
Volume of tissue compartment x (L)
- WP:
-
Well perfused tissues
- xBFR:
-
Bone Formation rate in bone tissue type x (cortical or trabecular).
- xBRR:
-
Bone Resorption rate in bone tissue type x (cortical or trabecular).
- xRVAF:
-
Intercompartmental clearance of Strontium from bone tissue x surface compartment into bone tissue x matrix compartment (cortical or trabecular).
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Acknowledgments and Disclosures
The authors wish to thank Dr Kayode Ogungbenro and Dr Aris Dokoutmetzidis for their useful comments and assistance with Matlab during model development.
The authors would like also to acknowledge Dr Isabelle Dupin-Roger, Dr Pascal Delrat and Dr Emmanuelle Foos-Gilbert for their useful comments on Strontium pharmacology and Strontium ranelate pharmacokinetics in rat.
Work in this paper was funded by Servier research and development and by the School of Pharmacy and Pharmaceutical Sciences, The University of Manchester.
Part of this work was presented by the authors at the 20th Population Approach Group Europe (PAGE) meeting in Athens, Greece, June 7–10, 2011.
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Appendix 1
Appendix 1
Tables of tissue concentrations and tissue-to-blood ratios from tissue distribution study.
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Pertinez, H., Chenel, M. & Aarons, L. A Physiologically Based Pharmacokinetic Model for Strontium Exposure in Rat. Pharm Res 30, 1536–1552 (2013). https://doi.org/10.1007/s11095-013-0991-x
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DOI: https://doi.org/10.1007/s11095-013-0991-x