(T1230-05-27) Human Pharmacokinetics Prediction for Trastuzumab Using Scaling and Two-Compartment Modeling with B-hFcRn Mice PK Data

Purpose: Biocytogen humanized neonatal Fc receptor mice (B-hFcRn mice) offer an alternative model for Tg32 mice in pharmacokinetic studies of biologics; however, differences between B-hFcRn and Tg32 mice raise uncertainties about whether data from B-hFcRn mice can reliably predict human pharmacokinetics.

Methods: Serum drug concentrations were measured using enzyme-linked immunosorbent assay (ELISA) in B-hFcRn mice following a single intravenous dose of 10 mg/kg Trastuzumab over 504 hours. Using allometric scaling, clearance (CL), intercompartmental clearance (Q), central volume of distribution (Vc), and peripheral volume of distribution (Vp) were extrapolated to humans. Additionally, the species-invariant time method (Dedrick Plot) was applied to predict human pharmacokinetic profiles. Pharmacokinetic parameters (CL, Q, Vc, and Vp) were calculated using a two-compartment model and scaled to humans.

Results: The extrapolated pharmacokinetic parameters and concentration-time profiles for humans showed accurate predictions within a 1.5-fold error. The concentration-time curve for a single 6 mg/kg dose of Trastuzumab was accurately forecasted up to approximately 200 hours in the mono-exponential elimination phase using the Dedrick Plot method. Using the two-compartment model, the human concentration-time profile was predicted, accurately reflecting up to 1006 hours post-administration, including both mono-exponential and bi-exponential elimination phases.

Conclusion: These findings demonstrate the ability to accurately predict human pharmacokinetics for Trastuzumab using preclinical data from B-hFcRn mice, showcasing the potential of this approach for early drug development and translational research.

References: 1.Low, B. E., Christianson, G. J., Lowell, E., Qin, W., & Wiles, M. V. (2020). Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human FCGRT transgenic mice. mAbs, 12(1), 1829334.
2.Nakamura, G., Ozeki, K., Takesue, H., Tabo, M., & Hosoya, K. I. (2021). Prediction of Human Pharmacokinetics Profile of Monoclonal Antibody Using hFcRn Transgenic Mouse Model. Biological & pharmaceutical bulletin, 44(3), 389–395.
3.Haraya, K., Ichikawa, T., Murao, N., Katada, H., & Kuramochi, T. (2025). Prediction of human pharmacokinetics of Fc-engineered therapeutic monoclonal antibodies using human FcRn transgenic mice. mAbs, 17(1), 2484443.

Acknowledgements: The authors declare that there are no conflicts of interest regarding the publication of this project.

Comparison of Observed and Simulated Human Serum Concentration-Time (C-T) Data for Trastuzumab at a Dose of 6 mg/kg on a Logarithmic Scale

Comparison of Observed and Simulated Human Serum Concentration-Time (C-T) Data for Trastuzumab at a Dose of 6 mg/kg on a Linear Scale