Model‐informed exploration of the boundaries of safe aluminium exposure from allergen immunotherapy in children

Background The safety of aluminium (Al) exposure from medicinal products for subcutaneous allergen immunotherapy (SCIT) is still under debate due to their administration in many doses over years. Especially for children, model‐informed risk assessment is urgently needed in the absence of clinical study data. Methods We applied a physiologically‐based toxicokinetic Al model for simulation of Al exposure from various SCIT scenarios in children (5 and 10 years) compared to adults (35 years) in addition to continuous Al exposure from dietary intake. Results Simulations of a worst‐case Al exposure scenario (five‐year SCIT; four‐weekly injections; 1.25 mg Al per dose) in children reveal substantial, but subtoxic and transient increases in bone Al content. Predicted increases of Al levels in the brain appear negligible. In both of these storage organs, Al levels predicted at 50 years of age were only marginally affected by the previous SCIT treatment. Two exceptional SCIT scenarios, prolongation of treatment duration to 40 years and parallel treatment with two 1.25 mg Al‐containing products, were associated with elevated bone Al levels above the normal adult range and close to a level where potential harm to bone metabolism cannot be excluded. Conclusions Simulations support the tolerability of single SCIT treatments in all age groups ≥5 years, also with respect to the long‐term Al body burden. The Pharmacopoeial limit of 1.25 mg Al per dose could be seen as a conservative threshold also for the sum of doses from parallel treatments. The decision to prolong therapy with Al‐containing SCIT products should be taken under careful consideration of Al accumulation.