Oral Bioavailability of Monoclonal Antibody

Background/Objectives: Despite significant interest in the oral delivery of antibodies, the oral bioavailability of monoclonal antibodies (mAbs) is not known to date. To find out an answer to this question, we have performed a preclinical investigation in mice and rats, using a non-binding humanized mAb trastuzumab as the prototype molecule. Methods: The antibody was administered at the dose of 100 mg/kg in mice and rats, and plasma pharmacokinetics (PK) was measured for 14 days. Published plasma PK of trastuzumab in mice and rats obtained after intravenous administration was also used for the analysis. Non-compartmental analysis (NCA), as well as compartmental modeling of PK data, was performed to estimate the oral bioavailability of the antibody in mice and rats. Results: It was found that the oral bioavailability of mAb in rats and mice determined using NCA was 0.027% and 0.014%, respectively. The model-estimated oral bioavailability of the mAb in rats and mice was 0.025% and 0.013%, respectively. The rate of absorption of the mAb from the gastrointestinal tract was found to be the same between rats and mice, as 0.78 h-1. Conclusions: Overall, the oral bioavailability of the humanized mAb in rodents was found to be around 0.02%, suggesting only 1 out of 5000 mAb molecules administered orally makes it to the systemic circulation. To the best of our knowledge, this is the first study to report an absolute oral bioavailability value for a mAb. It remains to be seen if the observed value of 0.02% is generalizable across mAb molecules and other animal species, including humans.