11/05/2026
This article presents a physiologically based pharmacokinetic (PBPK) model of niraparib developed to predict optimal dosage in patients with hepatic impairment. The model was built in PK‑Sim® using a comprehensive systematic review of niraparib pharmacokinetic data; key drug‑specific parameters were calibrated via an Approximate Bayesian Computation Sequential Monte Carlo (ABC‑SMC) approach. Hepatic impairment was captured by expressing carboxylesterase 1 (CES1) clearance as a function of total bilirubin.
Simulations under a 300 mg once‑daily regimen across mild, moderate, and severe hepatic impairment categories showed steady‑state total plasma AUC increases of 33%, 57%, 71% and 101% relative to normal. Dose adjustments to 250 mg (mild), 200 mg (moderate), and 150 mg (severe) brought predicted mean AUCs within ±20% of the value in patients with normal hepatic function receiving 300 mg. Sensitivity analysis identified pKa and CES1 specific clearance as the strongest determinants of tissue exposure. The validated PBPK model supports dose adjustment strategies for hepatic impairment and provides a quantitative framework for exploring niraparib safety and dosing in special populations.
