Early-phase clinical studies are typically designed to evaluate the safety, tolerability and PK of a novel molecule. The sample size and study duration are frequently inadequate for therapeutic efficacy assessment. However, pharmacodynamic (PD) biomarkers from early studies can provide valuable information of the intended target modulation by target therapeutics. Mechanistic modeling incorporating PD biomarker information greatly facilitates the rational dose and dosing regimen selection for efficacy trials in patients. One case study involves the utilization of a mechanistic PK model to project target receptor blockade for the design of a multi-national Phase 2 study. In another case study, simulations using a mechanistic PK-PD model supported a development decision to initiate a large confirmatory study in asthma patients.