In this presentation, the presenter will introduce the new IVIVE approach and compared its prediction performance with five literature in vitro prediction approaches. Drug unionized fractions at pH 7.0 and 7.4, protein/lipids binding in human plasma and milk, and Caco-2 or MDCK cell permeability in both directions were incorporated into the developed IVIVE model. A total of 71 drugs with published bilateral Caco-2 permeability data were used to test our IVIVE model. Compared with five in vitro prediction approaches reported in literature, the developed IVIVE approach provides a more accurate prediction of drug M/P ratios, especially for passive-diffusion drugs (88% predictions within 2-fold errors). The predictions for transporter substrates need further improvement, especially for the substrates of apical transporter (P-gp, MATEs and MCT-1) and drugs with an elimination half-life > 20 hours or < 2 hours.
The presenter will also introduce the mechanisms of therapeutic antibody/protein/peptide transfer from human blood to milk and review currently available human lactation data for FDA-approved therapeutic antibodies, proteins and peptides. The relationships between M/P ratio of therapeutic antibodies and FcRn binding affinity/elimination half-life were also tentatively investigated.
To understand the factors which affect drug or biologic transfer from a lactating woman’s blood to milk and potential risks to infants caused by therapeutic biologics in human milk.
To discuss current challenges in human M/P ratio prediction, especially for transporter substrates.
To understand the IVIVE model for the prediction of M/P ratios for small-molecule drugs.
To discuss the M/P ratios for therapeutic antibodies, proteins and peptides