Jean-René Jourdain Institute for Radiological Protection and Nuclear Safety IRSN, France

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1 PRIODAC, a project to determine the modalities and side effects of multiple administrations of stable iodine to protect people chronically exposed to radioactive iodine Jean-René Jourdain Institute for Radiological Protection and Nuclear Safety IRSN, France 7 th MELODI Workshop Next Generation Radiation Protection Research 11 November 2015 Munich, Germany

2 Background (1/4) In case of an accident occurring in a nuclear reactor, the massive release of radioactive iodines (iodine-131, short-lived iodines, tellurium) into the atmosphere can result in a risk of developing thyroid cancer in populations exposed, particularly in young children (nearly 7,000 cases reported in children after the Chernobyl accident in Belarus, Russia and Ukraine) The occurrence of thyroid cancer can be prevented by an administration of potassium iodide tablets (KI), as the stable iodine will block the uptake of radioactive iodines within the thyroid (in conjunction with other protective actions, i.e. evacuation, sheltering and food restrictions)

3 Background (2/4) Already in the 1970s, extensive studies showed that the effect of a single administration of 100 mg of KI to block the thyroid decreased quickly to less than 50% when KI was administered after 24h following radioiodines intake Also, it was showed that a KI dose of 100 mg per day administered over 1 week was considerably more protective than a KI dose of 200 mg once in 2 days or 200 mg once in 3 days Animal studies showed that KI doses comparable to those recommended for humans were efficient, and no adverse effects occurred during 11 days of repeated KI administrations From Reiners and Schneider 2013

4 Background (3/4) It was concluded that a daily dose of 1.5 mg of KI per kg of bodyweight optimally protects the thyroid of pregnant women, unborn babies and infants from exposure to radioactive iodines and that there are no adverse effects when KI is given for 10 days (Noteboom et al. 1997, Reiners and Schneider 2013) The most important observation concerning the incidence of KI-administration side effects has been made in Poland after the Chernobyl accident: KI administered in doses of 15 mg for newborns, 50 mg for children aged up to 5 years, 70 mg for minors older than 5 years and for pregnant & lactating women were distributed to 10.5 million children and 7 million adults in Poland (Nauman and Wolff 1993)

5 Background (4/4) According to a subsequent population-based survey of approximately 35,000 participants, only very few adverse effects were noted Reactions due to potassium iodide high sensitivity, including oedema and other dermatological or general adverse effects including headache, abdominal pain, diarrhoea, vomiting dyspnoea, were observed in 0.2% of the surveyed Polish population receiving stable iodine (Nauman and Wolff 1993) With respect to age-related effects, an elevated risk of thyroid dysfunctions among newborns and elderly people was suggested based on data of a literature review, but strong evidence was missing (Spallek et al. 2012) A high dose of KI may result in hypothyroidism, especially in newborns (Nishiyama et al. 2004)

6 Context (1/3) In France, the current marketing authorization (MA) of 65-mg KI tablets manufactured by the Military Central Pharmacy (PCA) authorizes a single administration that may be repeated only once if the evacuation of the population isn t possible The French MA of 130-mg KI tablets was obtained in 1997 on the basis of a well-established medical use; it was extended in 2009 for the 65-mg tablets without new supportive safety data The Fukushima accident has shown that repeated administrations of KI could be considered in case of chronic and/or repeated releases

7 Context (2/3) The modalities of KI repeated administrations (posology, frequency of administration, maximum dose that can be administered) should be determined for all categories of the population (newborns, children, adults, elderly, pregnant women, nursing mothers) and the associated side effects should be evaluated (obligation to update scientific data to reassess the benefit/risk ratio) The current French MA of KI was primarily based on bibliographic data from non-glp studies (Good Laboratory Practices) evaluating the acute toxicity in rats, mice and rabbits (studies of the 1960s)

8 Context (3/3) No documented mutagenicity and toxicology studies were presented for the French MA, except those related to the effects of repeated ingestions of KI in rats to assess the embryo-fetal and perinatal toxicity An extension of the current MA of KI requires: GLPs toxicology and pharmacology studies in two species Mutagenicity studies New data to reassess the benefit/risk ratio An extension of the marketing authorization of KI does not require clinical trials (antidote status of KI) if the efficacy is demonstrated in animals exposed and if new studies do not question the data published to date

9 Current Situation in the EU (1/2) In general, EU Member States are considering a second administration of stable iodine 24 hours on average after the first administration in the event of chronic releases Some EU Member States are considering a second stable iodine intake if the evacuation of population is impossible: Belgium, France Other EU Member States are considering a second stable iodine intake for some population groups: children (Finland), newborns and pregnant women (Norway), pregnant and nursing women (Italy) Other EU Member States are not considering a second stable iodine regardless the situation: The Netherlands

10 Current Situation in the EU (2/2) Bulgaria, Romania and Turkey recommend to not exceed a total dose of 1 gram of stable iodine (over a period of 10 days in Bulgaria and Romania) According to data from the literature, a lower second dose of stable iodine (e.g. 15 mg per day after an administration of 100 mg on the first day) would maintain a satisfactory level of thyroid protection while limiting the adverse effects of iodine (however, this strategy is not recommended for newborns, children, and pregnant women) The proposal of a maximum of 1 gram per person has to be explored

11 The PRIODAC Project PRIODAC: Repeated iodine prophylaxis in accidental situation Project involving 5 French partners Project supported by the French National Investment for the future funding programme (cofunding of 3.55 M ) 5-year project: 01/03/ /02/2019

12 Objectives of PRIODAC To determine modalities of repeated administrations of stable potassium iodide (KI) in a situation of chronic/repeated releases To reassess the associated side effects To better understand the molecular mechanisms regulating the metabolism of iodine To revise the regulatory French marketing authorization of 65-mg KI tablets To develop new recommendations related to the administration of KI towards a better international harmonization

13 Partners IRSN: Institute for Radiological Protection and Nuclear Safety, France CEA: Atomic and Alternative Energies Commission, France UNS: University of Nice Sophia Antipolis, France AMU: University of Aix Marseille, France PCA: Military Central Pharmacy, Army Medical Services, France The PRIODAC project is supported by the French National Investment for the future funding programme (cofunding of 3.55 M )

14 Principal Investigators IRSN: Isabelle Dublineau, Guillaume Phan, Maâmar Souidi, Jean-René Jourdain (coordinator of the project) CEA: Thierry Pourcher UNS: Jacques Darcourt AMU: Jean-Charles Martin PCA: Annick Pech ANR: Antony Lebeau In total, the PRIODAC project involves more than 20 scientists

15 IRSN UNS Administration modalities Pharmacokinetic studies PCA Side effects Clinical toxicology AMU IRSN CEA Regulation of iodine metabolism Action and transportation mechanisms UNS Toxicology regulatory studies Modification of the marketing authorization PCA IRSN Development of new recommendations Harmonization of European practices PCA

16 Experimental Strategy (1/2) Task 1: Define repeated stable iodine administration protocols (KI, potassium iodide) in people not previously exposed Assess the KI posology allowing a saturation of the thyroid promptly after the administration of stable iodine Determine the minimum effective dose leading to a thyroid saturation and demonstrate the efficacy of the dose determined in animals exposed Prevent excessive iodine accumulation to avoid side effects Study the administration modalities in Wistar rats representing the different categories of population

17 Experimental Strategy (2/2) Task 2: Assess possible side effects resulting from repeated administrations of KI and adapt when necessary the timeline of repeated administrations Task 3: Get benefit from pharmacokinetic and toxicology studies to better understand the mechanisms behind the regulation of iodine metabolism Task 4: Update the current marketing French authorization of KI and develop new recommendations for stable iodine prophylaxis

18 Timeline of the Project : To determine the modalities for repeated administrations of KI : To assess the side effects resulting from repeated administrations of KI : To gather new scientific knowledge with regards to the metabolism of stable iodine : To collate all required information with the view of obtaining a new marketing authorization for KI use in France 2019: To develop new recommendations for the use of KI in case of a nuclear accident

19 PRIODAC, a project to determine the modalities and side effects of multiple administrations of stable iodine to protect people chronically exposed to radioactive iodine Jean-René Jourdain Institute for Radiological Protection and Nuclear Safety IRSN, France 7 th MELODI Workshop Next Generation Radiation Protection Research 11 November 2015 Munich, Germany