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Integration of Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy into Model-Informed Dose Selection in
Mélanie Wilbaux1, Shu Yang2, Astrid Jullion3
1Pharmacometrics, Novartis, Basel, Switzerland.
Abstract:
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.
Insights
Model-informed dose selection using pharmacokinetics, pharmacodynamics, and safety data guided the development of FGF401, an FGFR4 inhibitor for cancer. This framework supports optimal dosing for future oncology trials.
Area of Science:
- Pharmacometrics and statistical modeling in oncology drug development.
- Pharmacokinetics (PK) and pharmacodynamics (PD) of targeted therapies.
- Clinical trial design and dose selection optimization.
Background:
- Model-informed dose selection is increasingly vital in early oncology clinical development.
- FGF401, a selective fibroblast growth factor receptor 4 (FGFR4) inhibitor, underwent comprehensive modeling and simulation (M&S) during its first-in-human trials.
- The M&S framework integrated PK, PD biomarkers, safety, and efficacy data.
Observation:
- A two-compartment population PK model with delayed absorption and linear elimination described FGF401 PK.
- Indirect PopPK/PD models were developed for FGF19 and C4 biomarkers, showing near-maximal PD effects at clinical exposure levels.
- Time-to-progression analysis suggested trough concentration-driven efficacy.
Findings:
- A PopPK/PD model demonstrated dose-dependent tumor growth inhibition.
- Exposure-safety analyses revealed no clinically relevant relationship between FGF401 exposure and on-target adverse events like elevated liver enzymes or diarrhea.
- Simulations confirmed maximal target inhibition and a lack of safety-exposure relationship for alanine aminotransferase.
Implications:
- The M&S framework successfully supported a FGF401 dose selection of 120 mg once daily.
- This integrated approach provides a practical model for dose selection in early oncology clinical development.
- Optimized dosing strategies enhance the efficiency and success of targeted cancer therapies.
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