Unlike the conventional toxicology approaches of NOAEL or NOEL for small molecules First-Time-In-Man (FTIM) dose selection, Minimal Anticipated Biological Effect Level (MABEL by EMEA) or Pharmacologically Active Dose (PAD by FDA) are widely adopted for biologics. In this presentation, PK-PD/pharmaco-statistical challenges in the application of MABEL or PAD methodologies will be enumerated and demonstrated with real-case illustrations. The first challenge of PK-PD modeling is to extrapolate animal PK profile to human PK profile, especially for antibody drugs. Target expression profile and target mediated drug clearance, differences between binding kinetics of surrogate molecule and candidate molecule, and allometric scaling should all be taken into considerations. Mechanistically/physiologically based PK-PD models play critical role in translating potential target-mediated toxicities and drug efficacies observed in relevant animal models into anticipated ones in human beings. Effective PK-PD models should also take target expression pattern in different tissues in both animal models and humans and examine delivery efficiency of biologics to their action site. In summary, PK-PD modeling with the above considerations can significantly enhance effective and appropriate use of MABEL or PAD methodologies in determining FTIM dose, with integrated quantitative measures of biologics actions in both relevant animal models and human beings.