Investigation of factors influencing radioiodine (131I) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach
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.
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 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)%.
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.
KeywordsRadioiodine uptake Variability Population model Benign thyroid disorders
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.
Compliance with ethical standards
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.
- 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 CrossRefPubMedGoogle 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
- 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 CrossRefPubMedGoogle 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 CrossRefGoogle 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 PubMedCrossRefGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar
- 24.Beal SSL, Boeckmann A, Bauer RJ (2009) NONMEM user’s guides. Icon development solutions, Ellicott City, pp 1989–2009Google 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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):603–607CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle Scholar