Personalized Romiplostim Therapy Through Intelligent Control Systems: Transforming Immune Thrombocytopenic Purpura Treatment

Abstract

Background: Immune thrombocytopenic purpura (ITP) treatment with romiplostim faces significant challenges due to complex dose-response relationships, inter-patient variability, and unpredictable external disturbances affecting platelet production. Traditional control approaches often fail to handle these uncertainties effectively, resulting in suboptimal therapeutic outcomes and increased safety risks.

Objective: To develop and validate an advanced Active Disturbance Rejection Control (ADRC) framework that optimizes romiplostim dosage regimens through intelligent disturbance estimation and rejection, enabling superior therapeutic outcomes despite system uncertainties and external perturbations.

Methods: We designed a novel third-order ADRC system incorporating enhanced Extended State Observer (ESO) for total disturbance estimation, nonlinear state error feedback (NLSEF) for robust control, and adaptive parameter tuning for personalized therapy. The framework integrates real-time platelet monitoring with dynamic interval scheduling (2-14 days) based on disturbance magnitude and patient response patterns. Comprehensive validation was performed using 150 virtual patients with realistic physiological variability across 32 weeks of treatment simulation using the validated pharmacokinetic-pharmacodynamic model from Tsai et al. [31].

Results: The advanced ADRC framework achieved remarkable performance improvements: time in therapeutic range increased to 91.7±6.4% versus 68.4±12.3% for conventional treatment (+34.1% improvement), platelet count variability reduced by 67.8%, total disturbance rejection capability exceeded 85%, bleeding episodes decreased by 78.4%, and emergency interventions reduced by 84.2%. The system demonstrated exceptional robustness under ±50% parameter uncertainty and multiple external disturbances.

Conclusions: The advanced ADRC framework represents a paradigm shift in ITP management, achieving unprecedented control performance through intelligent disturbance handling and enabling truly personalized therapy with superior safety profiles.