Identification of solubility-limited absorption of oral anticancer drugs using PBPK modeling based on rat PK and its relevance to human

•A PBPK analysis of rat pharmacokinetic data was utilized to identify drugs whose absorption are truly limited by solubility in the rat.•The proposed PBPK analysis of rat PK data based on 10 anti-cancer drugs showed good correlation between solubility-limited absorption in rat and human for 8 out of 10 model drugs.•This early identification of solubility-limited absorption in human has the potential to guide internal decisions on formulation development and on the need and timing of food effect and ARA studies, thereby saving valuable resources in drug development. Solubility is one of the key parameters that is optimized during drug discovery to ensure sufficient drug concentration in systemic circulation and to achieve the desired pharmacological response. We recently reported the application of PBPK analysis of early clinical pharmacokinetic data to identify drugs whose absorption are truly limited by solubility. In this work, we selected ten anticancer drugs that exhibit poor in vitro solubility to explore the utility of this approach to identify solubility-limited absorption based on rat pharmacokinetic data and compare the findings to human data. Oral rat pharmacokinetic studies were performed at the body weight-scaled doses of the model drugs’ human food effect studies, and analyzed using a top-down PBPK modeling approach. A good correlation of solubility-limited absorption in rat and human was observed. These results allow an early identification of drugs with truly solubility-limited absorption, with the potential to guide decisions and save valuable resources in drug development. [Display omitted]