A Digital Twin of the Angiotensin II Receptor Blocker Losartan: Physiologically Based Modeling of Blood Pressure Regulation

Losartan, a commonly prescribed angiotensin II receptor blocker (ARB) used to treat hypertension and heart failure, shows significant variability in pharmacokinetics (PK) and pharmacodynamics (PD) among individuals. In this study, we developed a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of losartan and its active metabolite, E3174, using curated data from 24 clinical trials. The model, implemented in SBML, mechanistically describes the processes of absorption, hepatic metabolism, renal excretion, and pharmacodynamic regulation via the renin–angiotensin–aldosterone system (RAAS). Simulation studies examined the effects of dose, hepatic and renal impairment, and genetic polymorphisms in CYP2C9 and ABCB1 on the model. The model successfully reproduced key PK/PD observations, including dose-dependent receptor blockade, attenuated responses with hepatic impairment, modest enhancement with renal impairment, and substantial variability in E3174 formation dependent on CYP2C9; the effects of ABCB1 were minimal. This mechanistic digital twin framework provides a quantitative basis for understanding variability in losartan therapy and supports its application in individualized dosing strategies.