Toxicology evaluation is one of the main requirements in bringing a drug candidate from pre-clinical to First-in-Human (FiH) studies. In the initial phase of the program, many compound properties are often not fully defined, such as purity, solid state form, and polymorphism, which can significantly impact the in vivo performance. Although only a small quantity of drug substance is available in the early stages, toxicology studies often require examining high doses, up to 1 to 2 g/kg. The intent is to achieve high in vivo exposure and assess adverse effects. In addition, the in vivo PK/PD studies are anticipated in the early phase with the objective to determine the clinical dose in human and evaluate the safety margin given that the robustness of the pharmacology model and translatability are often well established. However, the PK/PD relationship is often not fully validated early in the program. More than three quarters of new chemical entities in pharmaceutical research are poorly water soluble. For those compounds, solution formulation is often unachievable. Even when a solution can be prepared with high levels of excipients for pharmacokinetic studies, these complex formulations frequently cannot be tolerated in efficacy studies and often contribute some unacceptable excipient-related biological effects in the toxicology evaluation. Thus, a suitable formulation approach is needed to address these issues and to avoid delaying the transition of drug candidate from preclinical to FiH. A formulation plan to mitigate these challenges will be presented and discussed. The strategies are mainly focused on characterizing compound properties, categorizing compounds in the development classification system (DCS), and performing in vivo exposure optimization in the early pre-development phase to select an appropriate formulation for toxicology studies and FiH development.