Investigation of Antibody Pharmacokinetics in Male Reproductive System and Its Characterization Using a Translational PBPK Model

<b>Objectives:</b> To investigate the pharmacokinetics (PK) of the monoclonal antibody (mAb) in male reproductive tissues and develop a translational physiologically based pharmacokinetic (PBPK) model to characterize the PK data. <b>Method:</b> The PK of a non-cross-reactive antibody (trastuzumab) was investigated in human FcRn-expressing male mice following a 10 mg/kg intravenous dose. The PK in plasma and male reproductive tissues (i.e., epididymis, testes, vas deferens, seminal vesicles, and prostate glands) were evaluated. The observed PK data in mice were mathematically characterized using a novel PBPK model for antibodies that contained male reproductive systems. The mouse PBPK model was scaled to rats, monkeys, and humans to predict the PK of antibodies in male reproductive organs across animal species. <b>Results</b>: Plasma and tissue PK data generated in mice suggest that antibody distribution in male reproductive tissues is generally lower compared to that of most of the organs. The antibody exposure in the testes was 1.70%, in the epididymis was 2.57%, in the vas deferens was 2.01%, in the seminal vesicle was 0.42%, and in the prostate gland was 0.52% of the plasma exposure. The plasma and tissue PK data were simultaneously characterized using the PBPK model, which incorporated the novel male reproductive system. All the predicted PK profiles were within two-fold of the observed data, as indicated by percentage prediction error (%PE) values. The mouse model was successfully translated to bigger animals, and the model was used to simulate the PK of antibodies in rat, monkey, and human male reproductive systems. <b>Conclusions</b>: The combination of the experimental data and novel PBPK model presented here provides unprecedented insights into the antibody distributions in different male reproductive tissues. The PBPK model can serve as a crucial tool for advancing the development of antibody-based therapies for treating sexually transmitted infections (STIs), cancers, and contraceptives.