Key result
CYP2C9 reduced-function alleles increase losartan exposure up to ~3-fold in pharmacokinetic modeling.
Why the study?
Losartan exhibits significant interindividual variability in pharmacokinetics and pharmacodynamics, necessitating a mechanistic model to understand blood pressure regulation variability.
A mechanistic digital twin framework successfully predicts inter-individual variability in losartan pharmacokinetics and blood pressure response, providing a quantitative basis for individualized dosing strategies.
PBPK/PD model captures losartan PK/PD variability; leaves open prospective validation before guiding individualized dosing.
Background/Objectives: Losartan, an angiotensin II receptor blocker (ARB) used to treat hypertension and heart failure, shows significant variability in pharmacokinetics (PK) and pharmacodynamics (PD) among individuals. Methods: In this study, we developed a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of losartan and its active metabolite, E3174, using curated data from 25 clinical trials. The model mechanistically describes the processes of absorption, hepatic metabolism, renal and fecal excretion, and pharmacodynamic blood pressure regulation. Simulation studies examined the effects of dose, hepatic and renal impairment, and genetic polymorphisms in cytochrome p450 2C9 (CYP2C9) and P-glycoprotein 1, also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1), on the model. Results: 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. Specifically, dose dependency simulations confirmed the saturable nature of CYP2C9 metabolism, predicting a decreasing E3174-to-losartan ratio and a stronger, sustained suppression of blood pressure and aldosterone at higher doses. Hepatic impairment was predicted to lead to elevated losartan plasma concentrations (increased AUC) and attenuated metabolite formation, confirming the clinical need for dose reduction. Renal impairment simulations predicted stable losartan AUC but showed an overestimation of E3174 accumulation compared to observed data, where E3174 exposure remained stable. Genetic variability (CYP2C9) was the major determinant of response, with simulations confirming that reduced-function alleles lead to a 1.6- to 3-fold increase in losartan AUC and diminished blood pressure reduction. ABCB1 variability resulted in only minor modulation of systemic exposure and blood pressure effects. Conclusions: This mechanistic digital twin framework provides a quantitative basis for understanding variability in losartan therapy and supports its application in individualized dosing strategies.
No takes yet. Share an insight, caveat, or question.
Tensil et al. (2026) studied Hypertension and heart failure. Losartan was evaluated on Pharmacokinetic and pharmacodynamic effects (losartan AUC and blood pressure reduction). A physiologically based model of losartan showed that CYP2C9 genetic variability was the major determinant of response, with reduced-function alleles causing a 1.6- to 3-fold increase in losartan AUC.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: