Dosing Time Optimization of Enalapril and Propranolol through Inclusion of the Circadian Rhythm in Pharmacokinetic‐Pharmacodynamic Modeling

Abstract

Arterial hypertension is the modifiable risk factor that most affects mortality in the world. The diagnostic criteria and therapeutic objectives are based on average blood pressure (BP) values. However, BP shows a circadian variation, with an increase during the morning, a small postprandial valley, and a deeper night decrease. Several studies have shown that evening dosing of antihypertensive drugs significantly reduces BP during the night rest and even decreases the cardiovascular risk in the long-term compared to awakening dose. It has been suggested that the variation in the effect of enalapril and propranolol is due to circadian variations in the pharmacokinetics processes and therapeutic target. Pharmacokinetics (PK) - pharmacodynamics (PD) models of antihypertensive drugs have been developed to understand daytime effect changes. However, only the circadian variation in BP has been included and not the relevant pharmacokinetic variations. Furthermore, an algorithm able to find the optimal dosing time for a given starting BP circadian variation profile has not been proposed so far. This work proposes the inclusion of the circadian rhythm in the development of PK-PD models for enalapril and propranolol to evaluate and optimize the chronotherapy of arterial hypertension. To do this, a PK-PD model that includes the circadian rhythm was developed using data from published works. The parameters of the PK-PD models were estimated using a global optimization algorithm and, to assess the relevance of each parameter on the variables, sensitivity and identifiability analyses were performed. Subsequently, an optimization algorithm was created to propose an optimal dosing time. The most sensitive parameters were those related to the circadian rhythm. Optimization of the dosing time by maximizing the effect (total sum of BP reduction over 24 hrs.) indicates that the optimal time of administration is approximately 6:30 am for enalapril (~15% reduction) and 6:00 am for propranolol. However, maximizing the nocturnal fall resulted at 8:00 pm for enalapril (~27% reduction). By comparing the results obtained with the antecedents above, it can be noted that maximizing the effect does not necessarily imply a better therapeutic outcome. Since administration at bedtime has shown to reduce cardiovascular risk, which is consistent with maximizing the dipper percentage in this case. Finally, these analyses were performed using the reported data, which correspond to dipper patterns; however, the optimized times could change depending on the blood pressure profile of each patient.