Predicting drug-drug interaction and optimal dosing regimens of rivaroxaban combined with ceritinib using physiologically based pharmacokinetic and pharmacodynamic modeling.
TL;DR
The authors' model predicts that ceritinib co-administration substantially elevates rivaroxaban exposure and exploratory major bleeding risk, and predicts model-predicted dosing strategies comparable to standard monotherapy.
Abstract
Background
Direct oral anticoagulants like rivaroxaban are globally recommended for cancer-associated thrombosis. However, co-administration with the targeted ALK inhibitor ceritinib in lung cancer patients poses a critical risk of drug-drug interactions (DDI) due to potent CYP3A4 inhibition, lacking quantitative clinical assessments.
Objectives
To develop and validate physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models to quantitatively assess this specific DDI and provide model-predicted dosing strategies.
Methods
A hybrid "bottom-up" and "top-down" modeling strategy was employed within PK-Sim®. The rivaroxaban model integrated complex hepatic metabolic pathways (CYP3A4, CYP2J2, non-CYP hydrolysis) and active transport (P-gp, BCRP). The ceritinib model incorporated competitive and time-dependent CYP3A4 inhibition parameters. DDI simulations were conducted in a virtual Chinese population. The established model was applied to an exploratory clinical case, comparing its predictions against steady-state plasma concentrations determined via highly specific UPLC-MS/MS from a real-world ALK-positive non-small-cell lung cancer patient.
Results
Simulations demonstrated that concomitant administration of ceritinib (450 mg qd) increased rivaroxaban AUC by 52%-63% and Cmax by 49%-59%. Consequently, the exploratory risk of major bleeding elevated to 1.64- to 1.79-fold that of rivaroxaban monotherapy, aligning closely with observed clinical case data. However, reducing rivaroxaban from 20 mg qd to 12.5 mg qd (normal or mildly impaired renal function), and from 15 mg qd to 10 mg qd (moderate renal impairment), yielded exposure and bleeding risk comparable to standard monotherapy.
Conclusions
Our model predicts that ceritinib co-administration substantially elevates rivaroxaban exposure and exploratory major bleeding risk. Dose adjustment, alternative therapies, or close clinical monitoring are recommended to ensure patient safety.