Revisiting Fulvestrant Dosing: Biomarker-Driven Mathematical PK/PD Modeling and Dosing Optimization in Estrogen Receptor-Positive Breast Cancer

Computational pharmacokinetic/pharmacodynamic (PK/PD) models that quantitatively link dose, systemic exposure, target engagement, and biological response are essential for optimizing clinical efficacy. This study describes a biomarker-driven mathematical model developed to characterize the pharmacological effects of fulvestrant, a targeted estrogen receptor (ER) degrader used for the treatment of ER-positive breast cancer. Fulvestrant induces degradation of the oncogenic ER protein in tumors, thereby suppressing tumor growth and disease progression. So, optimizing dosing strategies to maximize intratumoral ER degradation is expected to improve therapeutic efficacy. The PK/PD model incorporated fulvestrant pharmacokinetic parameters (half-life: 14 h; clearance: 11 mL/kg/min), potency in tamoxifen-resistant cells (IC₅₀: 2.4 nM), tumor penetration (cell/plasma ratio: 0.7), plasma protein binding (∼99%), and intracellular ER turnover kinetics (0.003 h⁻¹). ER suppression and tumor growth inhibition (TGI) were modeled in xenograft mice at doses of 25 and 200 mg/kg, and model performance was refined through comparison with experimental in vivo TGI datasets. The preclinical framework was subsequently translated to humans and calibrated using reported clinical biomarker data obtained at the approved monthly intramuscular (IM) dose of 250 mg. Model simulations suggest that the historical 250 mg monthly regimen results in inadequate ER target engagement and is unlikely to achieve sustained tumor suppression in patients. Although the currently prescribed 500 mg monthly regimen improves target engagement, the model predicts that it still does not achieve sufficiently deep and sustained ER degradation. In contrast, simulations indicate that the optimal regimen of 200 mg weekly IM administration could reduce ER levels by >90% within six months and >99% within ten months, potentially resulting in substantially improved tumor control and clinical outcomes. The study further discusses the translational, safety, formulation, and clinical considerations associated with implementing this alternative dosing strategy.