Validation of an animal model for lactation transfer (including translation from animal to human using available human data) (D3.7)

After the first in vivo trial performed at UNIBO using Amoxicillin as test molecule (see Deliverable 3.5), WP3 scheduled 3 additional trials using other medicines, to evaluate the performances of the model with regards to different drug classes with varying physico-chemical characteristics. The chosen medicines, out of the ones thoroughly described in Deliverable 3.1, were metformin, levocetirizine and venlafaxine. Due to the relative absence of reliable literature data regarding their use in pigs, a preliminary PK study was performed at Ellegaard Göttingen Minipigs A/S on each drug, and results were used to select the correct dosages to administer. The study design, in terms of procedures and number of samplings, was kept identical to the one tailored for the amoxicillin study. Nonetheless, for these new trials, only Göttingen Minipigs sows were used, and the timing of the samplings were modified to suit the PK profile of each medicine. The studies took place at the experimental facility of the UNIBO between January and May 2023. Trying to maximize the in vivo trials and grant the best translational value, each medicine was administered at two different dosages throughout the trials: low dose for lactation week 2 and 3, and high dose for lactation week 4. Metformin and levocetirizine did not induce any side effects in both sows and piglets, while venlafaxine, already at the lowest dose, induced severe alterations in sows and litters that led to trial suspension during lactation week 3 in all animals. The results were consistent across sows and litters, and seem to suggest the applicability of the model to different medicines, with different physico-chemical features.

This deliverable also shows preliminary evaluations aimed at assessing the translatability of the results obtained in Minipigs to humans. To do so, the results from the preliminary amoxicillin study were used to develop a population pharmacokinetic (popPK) model, to estimate milk/plasma ratio (M/P). Due to the lack of reliable and standardized human data, lactation Physiologically-Based PharmacoKinetic (PBPK) models were developed in this species to simulate M/P ratio. The obtained M/P ratio for pigs and humans were very close, supporting the translational value of the proposed in vivo model.