Bioavailability of House Dust Mite Allergens in Sublingual Allergy Tablets Is Highly Dependent on the Formulation

Abstract

Background: In sublingual immunotherapy (SLIT), the immune system is addressed by solubilized allergen that interacts with immunocompetent cells of the oral mucosa, the efficiency of which is governed by 2 main factors of SLIT allergen bioavailability: the allergen concentration and the mucosal contact time. Recently, 3 house dust mite (HDM) SLIT tablets were developed that differ with regard to allergen content, nominal strength (maintenance doses: 6 SQ-HDM/10,000 Japanese Allergen Units [JAU], 12 SQ-HDM/ 20,000 JAU, and 300 IR/57,000 JAU), and formulation (freeze-dried/compressed). Here, the importance of the SLIT tablet formulation for HDM major allergen bioavailability is examined. Methods: The HDM major allergen content, tablet disintegration times, and allergen release kinetics were determined. Dissolution kinetics (allergen concentration vs. time) of Der f 1, Der p 1, and Der 2 were measured. Area under the curve (AUC) was used as a surrogate parameter for allergen bioavailability. Results: The release of HDM major allergens from the freeze-dried tablets was complete after 30 s, while only partial release was achieved with the compressed tablets, even after prolonged dissolution. At 1 min, i.e., the recommended sublingual holding time for the freeze-dried tablets, the allergen bioavailability (AUC) of the compressed 300 IR/57,000 JAU tablet was 4.7-fold (Der f 1), 10.8-fold (Der p 1), and 23.6-fold (Der 2) lower than that of the freeze-dried 12 SQ-HDM/20,000 JAU tablet and similar to (Der f 1) and 5.3-fold (Der p 1) and 12.5-fold (Der 2) lower than that of the freeze-dried 6 SQ-HDM/10,000 JAU tablet. Conclusions: SLIT tablet allergen bioavailability depends highly on the tablet formulation. Only the fast-dissolving freeze-dried tablets provide maximal delivery of soluble allergens and achieve allergen concentrations that reflect the nominal tablet strengths within the recommended sublingual holding time.

Persistent regulatory T‐cell response 2 years after 3 years of grass tablet SLIT: Links to reduced eosinophil counts, sIgE levels, and clinical benefit

“…Thus, these findings are only applicable to this product (grass extract freeze‐dried fast‐dissolving tablet formulation) and grass allergic patients and are not applicable to other products or different allergic disease conditions. The diversity of immunological mechanisms involved, with different dose/effect, unique pharmacologic profile, and a different bioavailability, makes extrapolation impossible and supports the need for performing independent investigations of the immunological mechanism for different immunotherapy products.…”

Clinical efficacy of sublingual immunotherapy tablets for allergic rhinitis is unlikely to be derived from in vitro allergen-release data

“…Disintegration times were~1 s versus 45 s for the 12 SQ HDM and 300 IR HDM SLIT tablets, respectively (p < 0.0001). Complete release of Der f 1, Der p 1 and Der 2 from the 12 SQ-HDM SLIT tablet was obtained within 30 s, whereas for the 300 IR HDM SLIT tablet, soluble HDM major allergen content continued to increase over time, but did not reach complete release, even after 10 minutes [29,30]. In contrast, using an in vitro dissolution assay endorsed by the European Pharmacopoeia (Ph.…”

The Bioavailability of Allergens in Allergy Tablets Depends on Several Factors

“…Ohashi-Doi et al [1] recently investigated the kinetics of allergen release from house dust mite (HDM) sublingual allergen immunotherapy (AIT) tablets that are commercially available from different manufacturers. They concluded, solely on the basis of in vitro dissolution data, that (i) the allergen bioavailability relies on the tablet formulation, and (ii) only freeze-dried versus compressed tablets provide maximal release of soluble allergens following sublingual administration.…”

“…Ohashi-Doi et al [1] compared the 3 aforementioned HDM AIT tablets only in terms of the kinetics of allergen release, and there was evidence of distinct dissolution properties in vitro. Specifically, HDM major allergen release is faster for Acarizax® and Miticure® than it appears to be for Actair®.…”

“…The latter conclusion also applies to major allergen assays. In any case, in vitro dissolution assays cannot be used as a surrogate of bioavailability unless an in vitro / in vivo correlation (IVIVC) is established (not the case in the study by Ohashi-Doi et al [1]).…”