Analysis of exposure margins in developmental toxicity studies for detection of human teratogens

• Published in: Regulatory toxicology and pharmacology Vol. 105; pp. 62 - 68
• Main Authors: Andrews, Paul A., Blanset, Diann, Costa, Priscila Lemos, Green, Martin, Green, Maia L., Jacobs, Abigail, Kadaba, Rajkumar, Lebron, Jose A., Mattson, Britta, McNerney, Mary Ellen, Minck, Daniel, Oliveira, Luana de Castro, Theunissen, Peter T., DeGeorge, Joseph J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2019
• Subjects: Developmental toxicity; Embryofetal; Exposure margins; Malformations; Pregnancy; Risk assessment; Teratogenicity; Cmax; Developmental toxicity; MRHD; AUC; ICH; Pregnancy; Malformations; Risk assessment; LOAEL; Teratogenicity; NOAEL; Embryofetal; MEFL; PK; GD; IMiDs; Exposure margins
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2019.04.005

The draft Step 2 ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high-dose in reproductive and developmental toxicity studies. To help determine an appropriate exposure margin for embryofetal developmental toxicity testing, a retrospective analysis was undertaken to determine what threshold would have been sufficient to detect hazards to embryofetal development in rats and rabbits for 18 known and 4 presumed human teratogens. The analysis showed that using a high dose that provided at least a 6-fold exposure margin in the developmental toxicity studies would have been sufficient to detect the teratogenic hazard with relevance for humans for all these therapeutics. With regards to human risk assessment practices for developmental toxicity, the analysis showed that, after excluding lenalidomide and pomalidomide data in rats, all available AUC margins at the NOAEL for the induction of malformations or embryofetal lethality were <4-fold of the exposure at the MRHD for all 22 therapeutics. These data support the proposed general approach of increased level of concern for human risk when exposure margins of the NOAEL to the MRHD are <10-fold, reduced concern when the exposure margins are 10- to 25-fold, and minimal concern when the exposure margin is > 25-fold. •A 6-fold exposure margin in developmental toxicity studies sufficed to detect teratogenic hazards for 22 human teratogens.•These data support the >25-fold exposure-based endpoint proposed by ICH for high-dose selection in DART studies.•Exposures at the NOAEL for induction of malformations or embryofetal lethality were <4-fold of the exposure at the MRHD.•These data support the ICH proposal of reduced concern for human risk when exposure margins at the NOAEL are >10-fold.