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

by Selleckchem | Aug 10 2023

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 (Ctrough )-driven efficacy requiring Ctrough 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.

Comments:

The paper discusses the application of a comprehensive modeling and simulation (M&S) framework in the early clinical development of FGF401, a selective fibroblast growth factor receptor 4 (FGFR4) inhibitor in oncology. The M&S framework integrates pharmacometrics and statistical methods to analyze and interpret pharmacokinetic (PK), pharmacodynamic (PD), safety, and efficacy data obtained from the first-in-human clinical trials of FGF401.

The pharmacokinetics of FGF401 were adequately described using a two-compartment population PK (PopPK) model with delayed 0-order absorption and linear elimination. This model allowed for a better understanding of how FGF401 is absorbed, distributed, metabolized, and eliminated in the body.

The pharmacodynamic effects of FGF401 were evaluated using indirect PopPK/PD models, which included a precursor compartment, for two biomarkers: circulating FGF19 and 7α-hydroxy-4-cholesten-3-one (C4). Model simulations indicated that the PD effects reached close to maximum at the clinically relevant exposure range, providing insights into the drug's mechanism of action and its potential efficacy.

The efficacy of FGF401 in terms of time-to-progression was analyzed using the Kaplan-Meier method. The analysis suggested that maintaining a trough concentration (Ctrough) above a specific threshold, close to the drug concentration required for 90% inhibition of phospho-FGFR4, was associated with favorable treatment outcomes.

Furthermore, a PopPK/PD model was developed to describe the dose-dependent effect of FGF401 on tumor growth. This model helped identify the optimal dose for inhibiting tumor growth effectively.

The M&S framework also included exposure-safety analyses to evaluate the relationship between FGF401 exposure and on-target adverse events such as elevation of aspartate aminotransferase and diarrhea. The analyses indicated a lack of clinically relevant relationship between FGF401 exposure and these adverse events, suggesting that the drug was generally well-tolerated within the studied dose range.

Overall, based on the insights gained from the M&S framework, a dose selection of 120 mg of FGF401 once daily, either in a fasted state or with a low-fat meal, was recommended for future development. The paper highlights the practical application of this M&S framework in oncology early clinical development and suggests that similar approaches could be broadly implemented in similar studies.