Systems Pharmacology Approach to Paroxysmal Nocturnal Hemoglobinuria: Quantitative Framework for Biomarker Dynamics across Multi-Mechanistic Therapies.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder driven by complement-mediated destruction of red blood cells. Although complement inhibitors have transformed PNH management, clinical responses vary across therapeutic classes because intravascular and extravascular hemolysis contribute differently to disease manifestations. Existing quantitative systems pharmacology (QSP) models of the complement system have improved understanding of PNH dynamics but primarily represent intravascular hemolysis and therefore do not fully explain biomarker patterns observed with all available treatments. In this study, we extend a published QSP model of the alternative complement pathway to incorporate mechanisms of extravascular hemolysis. The updated model integrates clinical pharmacokinetic and pharmacodynamic data from phase III trials of C5, C3, and factor B inhibitors and characterizes biomarker responses, including lactate dehydrogenase and circulating hemoglobin. By capturing both intravascular and extravascular processes, the model reproduces differences in therapeutic effects across complement inhibitor classes and provides a more complete mechanistic representation of complement-mediated hemolysis in PNH. The expanded model enables evaluation of drug targets throughout the complement cascade and supports prediction of biomarker dynamics, dose and regimen effects, and sources of patient variability. This work establishes a translational framework that can inform therapeutic development and guide the design of future studies for complement-mediated diseases.