Integration of Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy into Model‐Informed Dose Selection in Oncology First‐in‐Human Study: A Case of Roblitinib (FGF401)

Model‐informed dose selection has been drawing increasing interest in oncology early clinical development. The current paper describes the example of FGF401, a selective fibroblast growth factor receptor 4 (FGFR4) inhibitor, in which a comprehensive modeling and simulation (M&S) framework, using both pharmacometrics and statistical methods, was established during its first‐in‐human clinical development using the totality of pharmacokinetics (PK), pharmacodynamic (PD) biomarkers, and safety and efficacy data in patients with cancer. These M&S results were used to inform FGF401 dose selection for future development. A two‐compartment population PK (PopPK) model with a delayed 0‐order absorption and linear elimination adequately described FGF401 PK. Indirect PopPK/PD models including a precursor compartment were independently established for two biomarkers: circulating FGF19 and 7α‐hydroxy‐4‐cholesten‐3‐one (C4). Model simulations indicated a close‐to‐maximal PD effect achieved at the clinical exposure range. Time‐to‐progression was analyzed by Kaplan–Meier method which favored a trough concentration ( C trough )–driven efficacy requiring C trough above a threshold close to the drug concentration producing 90% inhibition of phospho‐FGFR4. Clinical tumor growth inhibition was described by a PopPK/PD model that reproduced the dose‐dependent effect on tumor growth. Exposure–safety analyses on the expected on‐target adverse events, including elevation of aspartate aminotransferase and diarrhea, indicated a lack of clinically relevant relationship with FGF401 exposure. Simulations from an indirect PopPK/PD model established for alanine aminotransferase, including a chain of three precursor compartments, further supported that maximal target inhibition was achieved and there was a lack of safety‐exposure relationship. This M&S framework supported a dose selection of 120 mg once daily fasted or with a low‐fat meal and provides a practical example that might be applied broadly in oncology early clinical development.