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

Abstract

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.

Keywords: adjuvants; allergen immunotherapy; aluminium; computer simulation; immunologic; patient safety; toxicokinetics.

FIGURE 1

Predictions of Al concentration time courses in plasma, bone, and brain from birth to adulthood following an average dietary Al exposure (“FOOD ONLY”) in a female population (solid line: Median; shaded areas: Quantiles).

FIGURE 2

Predictions of Al concentration time courses in the liver following all simulated SCIT scenarios (see Figures 3 and 4) in addition to the continuous background dietary exposure (solid line: Median; shaded areas: Quantiles; vertical shaded box: Time period of SCIT treatment; horizontal dashed line: Upper limit of normal (see Section 2); dotted line: Median time course of “FOOD ONLY” exposure (upper left panel)).

FIGURE 3

Predictions of Al concentration time courses in plasma, bone, and brain following a 5‐year SCIT treatment (Alhydrogel adjuvant type) during childhood (Child‐high‐Ahy5; left panel), adolescence (Adol‐high‐Ahy5; middle panel) and adulthood (Adult‐high‐Ahy‐5; right panel), each in addition to the continuous background dietary exposure (solid line: Median; colored shaded areas: Quantiles; vertical shaded box: Time period of SCIT treatment; horizontal dashed line: Upper limit of normal (ULN; see Section 2); dotted line: Median time course of “FOOD ONLY” exposure (see Figure 1)).

FIGURE 4

Predictions of Al concentration time courses in plasma, bone, and brain following SCIT treatments (Alhydrogel adjuvant type), either two consecutive 5‐year treatments during childhood (child‐high‐Ahy‐2 × 5; left panel), or “lifelong” treatment starting in adolescence (Adol‐high‐Ahy‐40; middle panel), or (C) two parallel 5‐year treatments during childhood (child‐2xhigh‐Ahy5; right panel), each in addition to the continuous background dietary exposure (solid line: Median; colored shaded areas: Quantiles; vertical shaded box: Time period of SCIT treatment; horizontal dashed line: Upper limit of normal (see Section 2); dotted line: Median time course of “FOOD ONLY” exposure (see Figure 1)).