Mathematical modeling of circadian parameters predicts that administering valsartan or aspirin at bedtime produces a more significant reduction in systemic vascular resistance and blood pressure than administration upon awakening.
Does the dosing time of valsartan and aspirin affect their antihypertensive effect in subjects with grade I or II essential hypertension?
Mathematical modeling suggests that bedtime administration of valsartan or aspirin maximizes their antihypertensive effects due to circadian variations in physiological regulation mechanisms.
Chronopharmacology of arterial hypertension impacts the long-term cardiovascular risk of hypertensive subjects. Therefore, clinical and computational studies have proposed optimizing antihypertensive medications' dosing time (Ta). However, the causes and mechanisms underlying the Ta-dependency antihypertensive effect have not been elucidated. Here we propose using a Ta- dependent effect model to understand and predict the antihypertensive effect of valsartan and aspirin throughout the day in subjects with grade I or II essential hypertension. The model based on physiological regulation mechanisms includes a periodic function for each parameter that changes significantly after treatment. Circadian variations of parameters depending on the dosing time allowed the determination of regulation mechanisms dependent on the circadian rhythm that were most relevant for the action of each drug. In the case of valsartan, it is the regulation of vasodilation and systemic vascular resistance. In the case of aspirin, the antithrombotic effect generates changes in the sensitivity of systemic vascular resistance and heart rate to changes in physical activity. Dosing time-dependent models predict a more significant effect on systemic vascular resistance and blood pressure when administering valsartan or aspirin at bedtime. However, circadian dependence on the regulation mechanisms showed different sensitivity of their circadian parameters and shapes of functions, presenting different phase shifts and amplitude. Therefore, different mechanisms of action and pharmacokinetic properties of each drug can generate different profiles of Ta-dependence of antihypertensive effect and optimal dosing times.
Cortés‐Ríos et al. (2023) studied Grade I or II essential hypertension (n=307). Valsartan and Aspirin vs. Awakening administration vs. bedtime administration was evaluated on Systemic vascular resistance (SVR) and blood pressure dynamics. Mathematical modeling of circadian parameters predicts that administering valsartan or aspirin at bedtime produces a more significant reduction in systemic vascular resistance and blood pressure than administration upon awakening.