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Updated: Aug 3, 2026
Models of Bone Metastasis
Published on: September 4, 2012
Model-informed dose selection for an investigational human epidermal growth factor receptor 2 antibody-drug conjugate
Yi Sun1, Chao Li2, Xingli Wang1
1Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China.
Aims:
The dose-escalation phase (phase Ia study) of a novel human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) FS-1502 included a dose range from 0.1 to 3.5 mg/kg in HER2-expressing advanced malignant solid tumours. However, the defined maximum tolerated dose was not reached. This model-informed approach integrated population pharmacokinetic (PopPK) modelling and exposure-response (E-R) analysis to facilitate dose selection for phase II.
Methods:
The PopPK model was constructed using PK data from 109 Chinese patients who received doses of 0.1-3.5 mg/kg FS-1502 every 3 (Q3W) or 4 weeks during a phase I dose-escalation and dose expansion trial. The structural model consisted of compartment models for FS-1502 and unconjugated monomethyl auristatin F. E-R was explored for the percentage change in tumour size, overall response rate and treatment-related adverse events.
Results:
A semi-mechanistic 2-analyte PopPK model was developed. The FS-1502 PK data were best described by a 2-compartment PK model with parallel linear and nonlinear Michaelis-Menten eliminations. The PK of unconjugated monomethyl auristatin F was described by a 2-compartment model with first-order elimination. E-R analysis supported the clinically meaningful efficacy of FS-1502 at 2.3 mg/kg and above. However, 2.3 mg/kg Q3W was considered to have a better benefit-risk balance due to a lower incidence of safety events without a significant reduction in efficacy compared to 3.0 mg/kg Q3W.
Conclusion:
This PopPK and E-R analysis guided the recommended phase II dose selection of 2.3 mg/kg Q3W and supported body weight-based dosing for an investigational HER2 ADC FS-1502.
Insights
Population pharmacokinetic and exposure-response analysis recommended a 2.3 mg/kg dose every 3 weeks for the novel HER2 antibody-drug conjugate FS-1502. This dose offers an optimal benefit-risk balance for patients with HER2-expressing advanced solid tumors.
Area of Science:
- Pharmacology
- Oncology
- Clinical Pharmacology
Background:
- A phase Ia study evaluated the novel human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC), FS-1502, in patients with HER2-expressing advanced malignant solid tumors.
- Dose escalation ranged from 0.1 to 3.5 mg/kg, but a maximum tolerated dose was not reached, necessitating further dose selection strategies.
Purpose of the Study:
- To integrate population pharmacokinetic (PopPK) modeling and exposure-response (E-R) analysis to determine the optimal dose for phase II trials.
- To identify a dose with a favorable benefit-risk profile for FS-1502 in HER2-expressing advanced solid tumors.
Main Methods:
- A semi-mechanistic 2-analyte PopPK model was developed using data from 109 Chinese patients treated with FS-1502 (0.1-3.5 mg/kg every 3 or 4 weeks).
- The model described the pharmacokinetics of FS-1502 and unconjugated monomethyl auristatin F.
- Exposure-response relationships were analyzed for tumor size changes, overall response rates, and treatment-related adverse events.
Main Results:
- The PopPK model indicated that FS-1502 PK is best described by a 2-compartment model with parallel linear and Michaelis-Menten eliminations.
- The PK of unconjugated monomethyl auristatin F was characterized by a 2-compartment model with first-order elimination.
- E-R analysis supported the efficacy of FS-1502 at 2.3 mg/kg and higher, with 2.3 mg/kg every 3 weeks showing a superior benefit-risk balance compared to 3.0 mg/kg every 3 weeks due to lower safety event incidence.
Conclusions:
- The PopPK and E-R analysis successfully guided the recommended phase II dose selection for FS-1502.
- A dose of 2.3 mg/kg every 3 weeks was recommended for phase II studies, supporting body weight-based dosing for this investigational HER2 ADC.
