TY - JOUR
T1 - Nonclinical regulatory immunotoxicity testing of nanomedicinal products
T2 - Proposed strategy and possible pitfalls
AU - Giannakou, Christina
AU - Park, Margriet V. D. Z.
AU - Bosselaers, Irene E. M.
AU - de Jong, Wim H.
AU - van der Laan, Jan Willem
AU - van Loveren, Henk
AU - Vandebriel, Rob J.
AU - Geertsma, Robert E.
PY - 2020/9
Y1 - 2020/9
N2 - Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation.This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in NanomedicineToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
AB - Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation.This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in NanomedicineToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
KW - ICH-S8
KW - immunotoxicity
KW - in vitro
KW - nanomedicinal product
KW - regulatory
KW - COMPLEMENT ACTIVATION
KW - SILVER NANOPARTICLES
KW - TISSUE DISTRIBUTION
KW - SKIN INTERACTIONS
KW - IN-VITRO
KW - TOXICITY
KW - INFLAMMASOME
KW - ACCUMULATION
KW - DISEASE
U2 - 10.1002/wnan.1633
DO - 10.1002/wnan.1633
M3 - (Systematic) Review article
C2 - 32266791
VL - 12
JO - Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology
JF - Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology
SN - 1939-5116
IS - 5
M1 - 1633
ER -