Skip to main content
SpringerLink
Log in

Investigation of factors influencing radioiodine (131I) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Radioiodine (131I) therapy is the common treatment option for benign thyroid diseases. The objective of this study was to characterize 131I biokinetics in patients with benign thyroid disease and to investigate and quantify the influence of patients’ demographic and clinical characteristics on intra-thyroidal 131I kinetics by developing a population model.

Methods

Population pharmacokinetic analysis was performed using a nonlinear mixed effects approach. Data sets of 345 adult patients with benign thyroid disease, retrospectively collected from patients’ medical records, were evaluated in the analysis. The two-compartment model of 131I biokinetics representing the blood compartment and thyroid gland was used as the structural model.

Results

Results of the study indicate that the rate constant of the uptake of 131I into the thyroid (ktu) is significantly influenced by clinical diagnosis, age, functional thyroid volume, free thyroxine in plasma (fT4), use of anti-thyroid drugs, and time of discontinuation of therapy before administration of the radioiodine (THDT), while the effective half-life of 131I is affected by the age of the patients. Inclusion of the covariates in the base model resulted in a decrease of the between subject variability for ktu from 91 (3.9) to 53.9 (4.5)%.

Conclusions

This is the first population model that accounts for the influence of fT4 and THDT on radioiodine kinetics. The model could be used for further investigations into the correlation between thyroidal exposure to 131I and the outcome of radioiodine therapy of benign thyroid disease as well as the development of dosing recommendations.

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

Similar content being viewed by others

References

  1. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA (2016) 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26(10):1343–1421. https://doi.org/10.1089/thy.2016.0229

    Article  PubMed  Google Scholar 

  2. Stokkel MP, Handkiewicz Junak D, Lassmann M, Dietlein M, Luster M (2010) EANM procedure guidelines for therapy of benign thyroid disease. Eur J Nucl Med Mol Imaging 37(11):2218–2228. https://doi.org/10.1007/s00259-010-1536-8

    Article  PubMed  Google Scholar 

  3. Silberstein EB, Alavi A, Balon HR, Clarke SE, Divgi C, Gelfand MJ, Goldsmith SJ, Jadvar H, Marcus CS, Martin WH, Parker JA, Royal HD, Sarkar SD, Stabin M, Waxman AD (2012) The SNMMI practice guideline for therapy of thyroid disease with 131I 3.0. J Nucl Med 53(10):1633–1651. https://doi.org/10.2967/jnumed.112.105148

    Article  PubMed  Google Scholar 

  4. Bonnema SJ, Hegedus L (2012) Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome. Endocr Rev 33(6):920–980. https://doi.org/10.1210/er.2012-1030

    Article  PubMed  CAS  Google Scholar 

  5. de Rooij A, Vandenbroucke JP, Smit JW, Stokkel MP, Dekkers OM (2009) Clinical outcomes after estimated versus calculated activity of radioiodine for the treatment of hyperthyroidism: systematic review and meta-analysis. Eur J Endocrinol 161(5):771–777. https://doi.org/10.1530/EJE-09-0286

    Article  PubMed  CAS  Google Scholar 

  6. Dietlein M, Grunwald F, Schmidt M, Schneider P, Verburg FA, Luster M (2016) Radioiodine therapy for benign thyroid diseases (version 5). German guideline. Nuklearmedizin 55(6):213–220. https://doi.org/10.3413/Nukmed-0823-16-04

    Article  PubMed  Google Scholar 

  7. Bernard D, Desruet MD, Wolf M, Roux J, Boin C, Mazet R, Gallazzini C, Calizzano A, Vuillez JP, Allenet B, Fagret D (2014) Radioiodine therapy in benign thyroid disorders. Evaluation of French nuclear medicine practices. Ann Endocrinol (Paris) 75(4):241–246. https://doi.org/10.1016/j.ando.2014.07.863

    Article  Google Scholar 

  8. Vaidya B, Williams GR, Abraham P, Pearce SH (2008) Radioiodine treatment for benign thyroid disorders: results of a nationwide survey of UK endocrinologists. Clin Endocrinol 68(5):814–820. https://doi.org/10.1111/j.1365-2265.2007.03097.x

    Article  Google Scholar 

  9. Hanscheid H, Canzi C, Eschner W, Flux G, Luster M, Strigari L, Lassmann M (2013) EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry II. Dosimetry prior to radioiodine therapy of benign thyroid diseases. Eur J Nucl Med Mol Imaging 40(7):1126–1134. https://doi.org/10.1007/s00259-013-2387-x

    Article  PubMed  CAS  Google Scholar 

  10. European Commission. Council Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation, and repealing Directives 89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom (2014). Off J Eur Union L13/2014 57:1-73. doi: https://doi.org/10.3000/19770677.L_2014.013.eng

  11. Bolch WE, Eckerman KF, Sgouros G, Thomas SR (2009) MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetry-standardization of nomenclature. J Nucl Med 50(3):477–484. https://doi.org/10.2967/jnumed.108.056036

    Article  PubMed  CAS  Google Scholar 

  12. Grayson RR (1960) Factors which influence the radioactive iodine thyroidal uptake test. Am J Med 28:397–415

    Article  PubMed  CAS  Google Scholar 

  13. Kobe C, Eschner W, Wild M, Rahlff I, Sudbrock F, Schmidt M, Dietlein M, Schicha H (2010) Radioiodine therapy of benign thyroid disorders: what are the effective thyroidal half-life and uptake of 131I? Nucl Med Commun 31(3):201–205. https://doi.org/10.1097/MNM.0b013e328333d303

    Article  PubMed  CAS  Google Scholar 

  14. Bonnema SJ, Fast S, Nielsen VE, Boel-Jorgensen H, Grupe P, Andersen PB, Hegedus L (2011) Serum thyroxine and age—rather than thyroid volume and serum TSH—are determinants of the thyroid radioiodine uptake in patients with nodular goiter. J Endocrinol Investig 34(3):e52–e57. https://doi.org/10.3275/7260

    Article  CAS  Google Scholar 

  15. Mariotti S, Franceschi C, Cossarizza A, Pinchera A (1995) The aging thyroid. Endocr Rev 16(6):686–715. https://doi.org/10.1210/edrv-16-6-686

    Article  PubMed  CAS  Google Scholar 

  16. Andrade VA, Gross JL, Maia AL (2001) The effect of methimazole pretreatment on the efficacy of radioactive iodine therapy in Graves’ hyperthyroidism: one-year follow-up of a prospective, randomized study. J Clin Endocrinol Metab 86(8):3488–3493. https://doi.org/10.1210/jcem.86.8.7707

    Article  PubMed  CAS  Google Scholar 

  17. Braga M, Walpert N, Burch HB, Solomon BL, Cooper DS (2002) The effect of methimazole on cure rates after radioiodine treatment for Graves’ hyperthyroidism: a randomized clinical trial. Thyroid 12(2):135–139. https://doi.org/10.1089/105072502753522365

    Article  PubMed  CAS  Google Scholar 

  18. Dunkelmann S, Kuenstner H, Nabavi E, Rohde B, Groth P, Schuemichen C (2007) Change in the intrathyroidal kinetics of radioiodine under continued and discontinued antithyroid medication in Graves’ disease. Eur J Nucl Med Mol Imaging 34(2):228–236. https://doi.org/10.1007/s00259-006-0234-z

    Article  PubMed  CAS  Google Scholar 

  19. Kyrilli A, Tang BN, Huyge V, Blocklet D, Goldman S, Corvilain B, Moreno-Reyes R (2015) Thiamazole pretreatment lowers the (131)I activity needed to cure hyperthyroidism in patients with nodular goiter. J Clin Endocrinol Metab 100(6):2261–2267. https://doi.org/10.1210/jc.2015-1026

    Article  PubMed  CAS  Google Scholar 

  20. Merle Y, Mentre F, Mallet A, Aurengo A (1993) Computer-assisted individual estimation of radioiodine thyroid uptake in Grave’s disease. Comput Methods Prog Biomed 40(1):33–41

    Article  CAS  Google Scholar 

  21. Areberg J, Jonsson H, Mattsson S (2005) Population biokinetic modeling of thyroid uptake and retention of radioiodine. Cancer Biother Radiopharm 20(1):1–10. https://doi.org/10.1089/cbr.2005.20.1

    Article  PubMed  CAS  Google Scholar 

  22. Merrill S, Horowitz J, Traino AC, Chipkin SR, Hollot CV, Chait Y (2011) Accuracy and optimal timing of activity measurements in estimating the absorbed dose of radioiodine in the treatment of Graves’ disease. Phys Med Biol 56(3):557–571. https://doi.org/10.1088/0031-9155/56/3/003

    Article  PubMed  CAS  Google Scholar 

  23. Massaro F, Vera L, Schiavo M, Lagasio C, Caputo M, Bagnasco M, Minuto F, Giusti M (2007) Ultrasonography thyroid volume estimation in hyperthyroid patients treated with individual radioiodine dose. J Endocrinol Investig 30(4):318–322. https://doi.org/10.1007/BF03346299

    Article  CAS  Google Scholar 

  24. Beal SSL, Boeckmann A, Bauer RJ (2009) NONMEM user’s guides. Icon development solutions, Ellicott City, pp 1989–2009

    Google Scholar 

  25. Keizer RJ, Karlsson MO, Hooker A (2013) Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose. CPT Pharmacometrics Syst Pharmacol 2:e50. https://doi.org/10.1038/psp.2013.24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Hanscheid H, Lassmann M, Reiners C (2011) Dosimetry prior to I-131-therapy of benign thyroid disease. Z Med Phys 21(4):250–257. https://doi.org/10.1016/j.zemedi.2011.01.006

    Article  PubMed  Google Scholar 

  27. Keizer R, Harling K, Karlsson MO (2012) Extended npde diagnostics for the between subjectvariability and residual error models. In: PAGE 21(2012). Abstracts of the Annual Meeting of the Population Approach Group in Europe. Abstr 2538. https://www.page-meeting.org/default.asp?abstract=2538

  28. Nguyen TH, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC, John J, Karlsson MO, Mould DR, Perez Ruixo JJ, Plan EL, Savic R, van Hasselt JG, Weber B, Zhou C, Comets E, Mentre F, Model Evaluation Group of the International Society of Pharmacometrics Best Practice C (2017) Model evaluation of continuous data pharmacometric models: metrics and graphics. CPT Pharmacometrics Syst Pharmacol 6(2):87–109. https://doi.org/10.1002/psp4.12161

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Savic RM, Karlsson MO (2009) Importance of shrinkage in empirical Bayes estimates for diagnostics: problems and solutions. AAPS J 11(3):558–569. https://doi.org/10.1208/s12248-009-9133-0

    Article  PubMed  PubMed Central  Google Scholar 

  30. Leggett RW (2010) A physiological systems model for iodine for use in radiation protection. Radiat Res 174(4):496–516. https://doi.org/10.1667/RR2243.1

    Article  PubMed  CAS  Google Scholar 

  31. Melo DR, Brill AB, Zanzonico P, Vicini P, Moroz B, Kwon D, Lamart S, Brenner A, Bouville A, Simon SL (2015) Organ dose estimates for hyperthyroid patients treated with (131)I: an update of the thyrotoxicosis follow-up study. Radiat Res 184(6):595–610. https://doi.org/10.1667/RR14160.1

    Article  PubMed  CAS  Google Scholar 

  32. Di Martino F, Traino AC, Brill AB, Stabin MG, Lazzer M (2002) A theoretical model for prescription of the patient-specific therapeutic activity for radioiodine therapy of Graves’ disease. Phys Med Biol 47(9):1493–1499

    Article  PubMed  Google Scholar 

  33. Bonnema SJ, Fast S, Hegedus L (2014) The role of radioiodine therapy in benign nodular goitre. Best Pract Res Clin Endocrinol Metab 28(4):619–631. https://doi.org/10.1016/j.beem.2014.02.001

    Article  PubMed  CAS  Google Scholar 

  34. de Bruin TW, Croon CD, de Klerk JM, van Isselt JW (1994) Standardized radioiodine therapy in Graves’ disease: the persistent effect of thyroid weight and radioiodine uptake on outcome. J Intern Med 236(5):507–513

    Article  PubMed  Google Scholar 

  35. Moka D, Dietlein M, Schicha H (2002) Radioiodine therapy and thyrostatic drugs and iodine. Eur J Nucl Med Mol Imaging 29(Suppl 2):S486–S491. https://doi.org/10.1007/s00259-002-0868-4

    Article  PubMed  CAS  Google Scholar 

  36. Bonnema SJ, Bennedbaek FN, Veje A, Marving J, Hegedus L (2006) Continuous methimazole therapy and its effect on the cure rate of hyperthyroidism using radioactive iodine: an evaluation by a randomized trial. J Clin Endocrinol Metab 91(8):2946–2951. https://doi.org/10.1210/jc.2006-0226

    Article  PubMed  CAS  Google Scholar 

  37. Walter MA, Christ-Crain M, Muller B, Muller-Brand J (2005) Radioiodine uptake and thyroid hormone levels on or off simultaneous carbimazole medication: a prospective paired comparison. Nuklearmedizin 44(1):33–36

    PubMed  CAS  Google Scholar 

  38. Sabri O, Zimny M, Schulz G, Schreckenberger M, Reinartz P, Willmes K, Buell U (1999) Success rate of radioiodine therapy in Graves’ disease: the influence of thyrostatic medication. J Clin Endocrinol Metab 84(4):1229–1233. https://doi.org/10.1210/jcem.84.4.5588

    Article  PubMed  CAS  Google Scholar 

  39. Urbannek V, Voth E, Moka D, Schicha H (2001) Radioiodine therapy of Graves’ disease—a dosimetric comparison of different strategies concerning antithyroid drugs. Nuklearmedizin 40(4):111–115

    Article  PubMed  CAS  Google Scholar 

  40. Berg GE, Michanek AM, Holmberg EC, Fink M (1996) Iodine-131 treatment of hyperthyroidism: significance of effective half-life measurements. J Nucl Med 37(2):228–232

    PubMed  CAS  Google Scholar 

  41. Connell JM, Hilditch TE, Robertson J, Coghill G, Alexander WD (1987) Radioprotective action of carbimazole in radioiodine therapy for thyrotoxicosis—influence of the drug on iodine kinetics. Eur J Nucl Med 13(7):358–361

    Article  PubMed  CAS  Google Scholar 

  42. Kubota S, Ohye H, Yano G, Nishihara E, Kudo T, Ito M, Fukata S, Amino N, Kuma K, Miyauchi A (2006) Two-day thionamide withdrawal prior to radioiodine uptake sufficiently increases uptake and does not exacerbate hyperthyroidism compared to 7-day withdrawal in Graves’ disease. Endocr J 53(5):603–607

    Article  PubMed  CAS  Google Scholar 

  43. Zakavi SR, Khazaei G, Sadeghi R, Ayati N, Davachi B, Bonakdaran S, Jabbari Nooghabi M, Moosavi Z (2015) Methimazole discontinuation before radioiodine therapy in patients with Graves’ disease. Nucl Med Commun 36(12):1202–1207. https://doi.org/10.1097/MNM.0000000000000384

    Article  PubMed  CAS  Google Scholar 

  44. Reinhardt MJ, Brink I, Joe AY, Von Mallek D, Ezziddin S, Palmedo H, Krause TM (2002) Radioiodine therapy in Graves’ disease based on tissue-absorbed dose calculations: effect of pre-treatment thyroid volume on clinical outcome. Eur J Nucl Med Mol Imaging 29(9):1118–1124. https://doi.org/10.1007/s00259-002-0877-3

    Article  PubMed  CAS  Google Scholar 

  45. Oddie TH, Meade JH Jr, Myhill J, Fisher DA (1966) Dependence of renal clearance of radioiodide on sex, age and thyroidal status. J Clin Endocrinol Metab 26(12):1293–1296. https://doi.org/10.1210/jcem-26-12-1293

    Article  PubMed  CAS  Google Scholar 

  46. Morsch EP, Vanacor R, Furlanetto TW, Schmid H (2011) Two weeks of a low-iodine diet are equivalent to 3 weeks for lowering urinary iodine and increasing thyroid radioactive iodine uptake. Thyroid 21(1):61–67. https://doi.org/10.1089/thy.2010.0232

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, Faculty of Medicine, University of Banja Luka, Save Mrkalja 14, 78000, Banja Luka, Bosnia and Herzegovina

    Valentina Topić Vučenović & Dijana Jelić

  2. Institute of Nuclear Medicine and Thyroid Gland Disease, University Clinical Centre of the Republic of Srpska, 12 beba bb, 78000, Banja Luka, Bosnia and Herzegovina

    Zvezdana Rajkovača, Dragi Stanimirović & Goran Vuleta

  3. Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, Belgrade, 11000, Serbia

    Branislava Miljković & Katarina Vučićević

Authors
  1. Valentina Topić Vučenović
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zvezdana Rajkovača
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dijana Jelić
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dragi Stanimirović
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Goran Vuleta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Branislava Miljković
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katarina Vučićević
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

V.T.V. gathered data, performed analysis, interpreted the results, and wrote the manuscript; Z.R., G.V., and D.S. designed the study and interpreted results; D.J. designed the study and revised the manuscript; B.M. supervised the study and revised the manuscript; K.V. performed the analysis and wrote the manuscript.

Corresponding author

Correspondence to Valentina Topić Vučenović.

Ethics declarations

The study protocol was approved by the Ethics Committee of the University Clinical Centre of the Republic of Srpska and all procedures were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For the retrospective type of study, formal consent is not required.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 487 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Topić Vučenović, V., Rajkovača, Z., Jelić, D. et al. Investigation of factors influencing radioiodine (131I) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach. Eur J Clin Pharmacol 74, 1037–1045 (2018). https://doi.org/10.1007/s00228-018-2459-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-018-2459-8

Keywords

Search

Navigation