Skip to main content

Advertisement

SpringerLink
Log in

A Physiologically Based Pharmacokinetic Model for Strontium Exposure in Rat

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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).

References

  1. Shorr E, Carter AC. The usefulness of strontium as an adjuvant to calcium in the remineralization of the skeleton in man. Bull Hosp Joint Dis. 1952;13(1):59–66.

    PubMed  CAS  Google Scholar 

  2. McCaslin FE, Janes HM. The effect of strontium lactate in the treatment of osteoporosis. Mayo Clin Proc. 1959;34:329–34.

    Google Scholar 

  3. An YH, RJ. F. Animal Models in Orthopaedic Research. Animal Models in Orthopaedic Research 1998.

  4. Ammann P. Strontium ranelate: a physiological approach for an improved bone quality. Bone. 2006;38(2 Suppl 1):15–8.

    Article  PubMed  Google Scholar 

  5. Marie PJ, Hott M, Modrowski D, De Pollak C, Guillemain J, Deloffre P, et al. An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogen-deficient rats. J Bone Miner Res. 1993;8(5):607–15.

    Article  PubMed  CAS  Google Scholar 

  6. Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int. 2001;69(3):121–9.

    Article  PubMed  CAS  Google Scholar 

  7. Ammann P. Strontium ranelate: a novel mode of action leading to renewed bone quality. Osteoporos Int. 2005;16 Suppl 1:S11–5.

    Article  PubMed  CAS  Google Scholar 

  8. Marie PJ. Strontium ranelate: a novel mode of action optimizing bone formation and resorption. Osteoporos Int. 2005;16 Suppl 1:S7–S10.

    Article  PubMed  CAS  Google Scholar 

  9. Grynpas MD, Hamilton E, Cheung R, Tsouderos Y, Deloffre P, Hott M, et al. Strontium increases vertebral bone volume in rats at a low dose that does not induce detectable mineralization defect. Bone. 1996;18(3):253–9.

    Article  PubMed  CAS  Google Scholar 

  10. Busse B, Jobke B, Hahn M, Priemel M, Niecke M, Seitz S, et al. Effects of strontium ranelate administration on bisphosphonate-altered hydroxyapatite: Matrix incorporation of strontium is accompanied by changes in mineralization and microstructure. Acta Biomater. 2010;6(12):4513–21.

    Article  PubMed  CAS  Google Scholar 

  11. Jobke B, Burghardt AJ, Muche B, Hahn M, Semler J, Amling M, et al. Trabecular reorganization in consecutive iliac crest biopsies when switching from bisphosphonate to strontium ranelate treatment. PLoS One. 2011;6(8):e23638.

    Article  PubMed  CAS  Google Scholar 

  12. Canalis E, Hott M, Deloffre P, Tsouderos Y, Marie PJ. The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone. 1996;18(6):517–23.

    Article  PubMed  CAS  Google Scholar 

  13. Takahashi N, Sasaki T, Tsouderos Y, Suda T. S 12911–2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res. 2003;18(6):1082–7.

    Article  PubMed  CAS  Google Scholar 

  14. Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350(5):459–68.

    Article  PubMed  CAS  Google Scholar 

  15. Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90(5):2816–22.

    Article  PubMed  CAS  Google Scholar 

  16. Reginster JY, Kaufman JM, Goemaere S, Devogelaer JP, Benhamou CL, Felsenberg D, et al. Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis. Osteoporos Int. 2011 Nov 29.

  17. Stepensky D, Kleinberg L, Hoffman A. Bone as an effect compartment: models for uptake and release of drugs. Clin Pharmacokinet. 2003;42(10):863–81.

    Article  PubMed  CAS  Google Scholar 

  18. Pors NS. The biological role of strontium. Bone. 2004;35(3):583–8.

    Article  Google Scholar 

  19. Dahl SG, Allain P, Marie PJ, Mauras Y, Boivin G, Ammann P, et al. Incorporation and distribution of strontium in bone. Bone. 2001;28(4):446–53.

    Article  PubMed  CAS  Google Scholar 

  20. Marie PJ. Strontium as therapy for osteoporosis. Curr Opin Pharmacol. 2005;5(6):633–6.

    Article  PubMed  CAS  Google Scholar 

  21. Apostoaei AI. Absorption of strontium from the gastrointestinal tract into plasma in healthy human adults. Health Phys. 2002;83(1):56–65.

    Article  PubMed  CAS  Google Scholar 

  22. Moraes ME, Aronson JK, Grahame-Smith DG. Intravenous strontium gluconate as a kinetic marker for calcium in healthy volunteers. Br J Clin Pharmacol. 1991;31(4):423–7.

    Article  PubMed  CAS  Google Scholar 

  23. Samachson J. The gastrointestinal clearance of Strontium-85 and calcium-45 in man. Radiat Res. 1966;27(1):64–74.

    Article  CAS  Google Scholar 

  24. Samachson J, Spencer-Laszlo H. Urinary excretion of calcium and Strontium-85 in man. J Appl Phys. 1962;17:525–30.

    CAS  Google Scholar 

  25. Walser M. Renal Excretion of Alkaline Earths. In: Comar CL, Bronner F, editors. Mineral Metabolism. An Advanced Treatise. Chapter IV. New York: Academic; 1969. p. 235–320.

    Google Scholar 

  26. Mundy GR, Martin TJ. Physiology and pharmacology of bone. Physiology and pharmacology of bone: Handbook of experimental pharmacology; v 107. 1993:xxv, 762.

  27. O’Flaherty EJ. Physiologically based models of metal kinetics. Crit Rev Toxicol. 1998;28(3):271–317.

    Article  PubMed  Google Scholar 

  28. Staub JF, Foos E, Courtin B, Jochemsen R, Perault-Staub AM. A nonlinear compartmental model of Sr metabolism. I. Non-steady-state kinetics and model building. Am J Physiol Regul Integr Comp Physiol. 2003;284(3):R819–34.

    PubMed  CAS  Google Scholar 

  29. Staub JF, Foos E, Courtin B, Jochemsen R, Perault-Staub AM. A nonlinear compartmental model of Sr metabolism. II. Its physiological relevance for Ca metabolism. Am J Physiol Regul Integr Comp Physiol. 2003;284(3):R835–52.

    PubMed  CAS  Google Scholar 

  30. Leggett RW. A generic age-specific biokinetic model for calcium-like elements. Radiat Prot Dosim. 1992;41(2–4):183–98.

    CAS  Google Scholar 

  31. Leeuwenkamp OR, van der Vijgh WJ, Husken BC, Lips P, Netelenbos JC. Quantification of strontium in plasma and urine with flameless atomic absorption spectrometry. Clin Chem. 1989;35(9):1911–4.

    PubMed  CAS  Google Scholar 

  32. D’Haese PC, Van Landeghem GF, Lamberts LV, Bekaert VA, Schrooten I, De Broe ME. Measurement of strontium in serum, urine, bone, and soft tissues by Zeeman atomic absorption spectrometry. Clin Chem. 1997;43(1):121–8.

    PubMed  Google Scholar 

  33. Barto R, Sips AJ, van der Vijgh WJ, Netelenbos JC. Sensitive method for analysis of strontium in human and animal plasma by graphite furnace atomic absorption spectrophotometry. Clin Chem. 1995;41(8 Pt 1):1159–63.

    PubMed  CAS  Google Scholar 

  34. Nestorov I. Whole body pharmacokinetic models. Clin Pharmacokinet. 2003;42(10):883–908.

    Article  PubMed  CAS  Google Scholar 

  35. O’Flaherty EJ. Physiologically based models for bone-seeking elements. I. Rat skeletal and bone growth. Toxicol Appl Pharmacol. 1991;111(2):299–312.

    Article  PubMed  Google Scholar 

  36. O’Flaherty EJ. Physiologically based models for bone-seeking elements. II. Kinetics of lead disposition in rats. Toxicol Appl Pharmacol. 1991;111(2):313–31.

    Article  PubMed  Google Scholar 

  37. Zucker TF. The Growth Curve of the albino rat in relation to diet. J Nutr. 1941.

  38. Mundy GR. Cellular and molecular regulation of bone turnover. Bone. 1999;24(5 Suppl):35S–8S.

    Article  PubMed  CAS  Google Scholar 

  39. Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093–5.

    Article  PubMed  CAS  Google Scholar 

  40. Jones HM, Parrott N, Jorga K, Lave T. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet. 2006;45(5):511–42.

    Article  PubMed  CAS  Google Scholar 

  41. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health. 1997;13(4):407–84.

    PubMed  CAS  Google Scholar 

  42. Nestorov IA, Aarons LJ, Arundel PA, Rowland M. Lumping of whole-body physiologically based pharmacokinetic models. J Pharmacokinet Biopharm. 1998;26(1):21–46.

    Article  PubMed  CAS  Google Scholar 

  43. Landaw EM, DiStefano 3rd JJ. Multiexponential, multicompartmental, and noncompartmental modeling. II. Data analysis and statistical considerations. Am J Physiol. 1984;246(5 Pt 2):R665–77.

    PubMed  CAS  Google Scholar 

  44. Ette EI, Williams PJ. Population pharmacokinetics II: estimation methods. Ann Pharmacother. 2004;38(11):1907–15.

    Article  PubMed  CAS  Google Scholar 

  45. Gibaldi M, Perrier D. Pharmacokinetics (2nd ed.). 1982.

  46. Comar CL, Georgi J. Assessment of chronic exposure to radiostrontium by urinary assay. Nature. 1961;191:390–1.

    Article  PubMed  CAS  Google Scholar 

  47. Comar CL, Nold MM, Wasserman RH. Strontium-calcium discrimination factors in the rat. Proc Soc Exp Biol Med. 1956;92(4):859–63.

    PubMed  CAS  Google Scholar 

  48. Aarons L. Physiologically based pharmacokinetic modelling: a sound mechanistic basis is needed. Br J Clin Pharmacol. 2005;60(6):581–3.

    Article  PubMed  CAS  Google Scholar 

  49. O’Flaherty EJ. Physiologically based models for bone-seeking elements. III. Human skeletal and bone growth. Toxicol Appl Pharmacol. 1991;111(2):332–41.

    Article  PubMed  Google Scholar 

  50. O’Flaherty EJ. Physiologically based models for bone-seeking elements. IV. Kinetics of lead disposition in humans. Toxicol Appl Pharmacol. 1993;118(1):16–29.

    Article  PubMed  Google Scholar 

  51. Lemaire V, Tobin FL, Greller LD, Cho CR, Suva LJ. Modeling the interactions between osteoblast and osteoclast activities in bone remodeling. J Theor Biol. 2004;229(3):293–309.

    Article  PubMed  CAS  Google Scholar 

  52. Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, et al. Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem. 2003;278(50):50259–72.

    Article  PubMed  CAS  Google Scholar 

  53. Cox EH, Veyrat-Follet C, Beal SL, Fuseau E, Kenkare S, Sheiner LB. A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron. J Pharmacokinet Biopharm. 1999;27(6):625–44.

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Molecular and Clinical Pharmacology, The University of Liverpool, Block H, 1st Floor 70 Pembroke Place, Liverpool, L60 3CE, UK

    Henry Pertinez

  2. Clinical Pharmacokinetic Department, Institut de Recherches Internationales Servier, Suresnes Cedex, France

    Marylore Chenel

  3. Centre for Applied Pharmacokinetic Research School of Pharmacy and Pharmaceutical sciences, The University of Manchester, Manchester, UK

    Leon Aarons

Authors
  1. Henry Pertinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marylore Chenel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leon Aarons
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henry Pertinez.

Appendix 1

Appendix 1

Tables of tissue concentrations and tissue-to-blood ratios from tissue distribution study.

Table VII Mean Strontium Tissue Concentrations Strontium Rat Tissue Distribution Study
Full size table
Table VIII Strontium Tissue to Blood Ratios at 2 h After Final Dose in Strontium Rat Tissue Distribution Study
Full size table

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-0991-x

KEY WORDS

Search

Navigation