Report on scope and limitations of in vivo and in vitro non-clinical and computational models for drug milk excretion and breastfed infant exposure; Selection of a panel of at least 10 model compounds for initial evaluation of non-clinical models

Task 3.1: Literature search (M1-M6) (UNIBO, TEVA, KUL, CHUT, UNIGE UOSL, Bionotus, Covance, Ellegaard, NVS). First, literature searches will be conducted on: (i) lactation characteristics of non-clinical tox species (anatomy/histological structures, milk composition, duration of lactation); (ii) non-clinical (in vivo and in vitro) lactation models; (iii) computational approaches to determine drug milk excretion; (iv) non-clinical data available on concentration of drugs in milk, pup exposure; (v) human lactation data, in collaboration with WP4, including milk-mediated drug exposure in breastfed infants (as a benchmark for predictions generated in this WP; possible link to WP4 if/when human lactation data would be available). This knowledge mapping effort should reveal the current state-of-the art including limitations and shortcomings. This will aid in defining a consensus and starting points for development and characterisation of fit-for-purpose non-clinical (in vitro human & in vivo animal) and computational (in silico) models (subsequent tasks in this WP). Information gathered will be combined in structured overviews of existing non-clinical and computational models and clinical reference data on lactation and risk assessment of drug exposure in breastfed infants. The structured overview will be an important technical information source for selection of a set of 10 therapeutically relevant model drugs that will be used in subsequent tasks in this WP, i.e. for assessment of model performance and applicability (Task 3.2-3.4). Criteria for selection of model drugs will be: (i) different chemical structures, physicochemical properties; (ii) different modalities (both LMW and biologicals); (iii) clinical relevance including medical need in the pregnant population; (iv) quality and resolution of available reference data; (v) clinical data sets for which a robust popPK model is available; (vi) availability of PK data; (vii) consider the model drugs that would be(come) available from EFPIA partners and, if possible (dependent on timelines), in WP4 (the demonstration projects in WP4 will generate data sets on breast milk concentrations for selected model drugs).