Clinical therapeutics · 2026
Physiologically Based Pharmacokinetic Model for Fluzoparib Among Patients With Renal Impairment.
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Yang Yi, Chen Song, Xiang Qiulin, Li Guoxing, Yang Yingying, Li Shaorong, Rao Jing, Yu Xian
Аннотация
PURPOSE: Currently, no pharmacokinetic (PK) studies or dosing guidelines exist for fluzoparib in cancer patients with moderate to severe renal impairment. This study aimed to develop a physiologically based PK (PBPK) model to assess the impact of renal impairment on fluzoparib exposure and to propose adjusted dosing regimens for this patient population.
METHODS: Fluzoparib's physicochemical and Absorption, Distribution, Metabolism, and Excretion parameters were obtained from literature and DrugBank. Published drug concentration-time data were digitized using GetData software. PBPK models for healthy adults and adults with renal impairment were developed and validated within PK-Sim software using clinical data. The verified models simulated plasma exposure to inform dosing recommendations for patients with renal impairment.
FINDINGS: A robust PBPK model for fluzoparib in healthy adults was established and validated, with predicted concentration-time curves showing good agreement with observed data. The ratios of simulated to observed Cmax and AUC0-t were within twofold. Simulations indicated that, compared to healthy subjects, severe renal impairment increased fluzoparib Cmax and AUC0-t by 0.99- and 2.01-fold, respectively. The model suggested that dose adjustment is unnecessary for mild renal impairment. However, reduced doses are required for patients with moderate and severe renal impairment to achieve plasma exposure levels comparable to those in subjects with normal renal function.
IMPLICATIONS: This study successfully established and validated PBPK models for fluzoparib in adults with varying renal function. The simulations indicate that while no dose modification is needed for mild renal impairment, dose reduction is warranted for moderate and severe impairment to maintain equivalent systemic exposure. In the absence of clinical trial data, these findings provide a preliminary reference for dosing fluzoparib in cancer patients with renal impairment.
METHODS: Fluzoparib's physicochemical and Absorption, Distribution, Metabolism, and Excretion parameters were obtained from literature and DrugBank. Published drug concentration-time data were digitized using GetData software. PBPK models for healthy adults and adults with renal impairment were developed and validated within PK-Sim software using clinical data. The verified models simulated plasma exposure to inform dosing recommendations for patients with renal impairment.
FINDINGS: A robust PBPK model for fluzoparib in healthy adults was established and validated, with predicted concentration-time curves showing good agreement with observed data. The ratios of simulated to observed Cmax and AUC0-t were within twofold. Simulations indicated that, compared to healthy subjects, severe renal impairment increased fluzoparib Cmax and AUC0-t by 0.99- and 2.01-fold, respectively. The model suggested that dose adjustment is unnecessary for mild renal impairment. However, reduced doses are required for patients with moderate and severe renal impairment to achieve plasma exposure levels comparable to those in subjects with normal renal function.
IMPLICATIONS: This study successfully established and validated PBPK models for fluzoparib in adults with varying renal function. The simulations indicate that while no dose modification is needed for mild renal impairment, dose reduction is warranted for moderate and severe impairment to maintain equivalent systemic exposure. In the absence of clinical trial data, these findings provide a preliminary reference for dosing fluzoparib in cancer patients with renal impairment.