Dosing time optimization of antihypertensive medications by including the circadian rhythm in pharmacokinetic-pharmacodynamic models

Blood pressure (BP) follows a circadian variation, increasing during active hours, showing a small postprandial valley and a deeper decrease during sleep. Nighttime reduction of 10-20% relative to daytime BP is defined as a dipper pattern, and a reduction of less than 10%, as a non-dipper pattern. Despite this BP variability, hypertension's diagnostic criteria and therapeutic objectives are usually based on BP average values. Indeed, studies have shown that chrono-pharmacological optimization significantly reduces long-term cardiovascular risk if a BP dipper pattern is maintained. Changes in the effect of antihypertensive medications can be explained by circadian variations in their pharmacokinetics (PK) and pharmacodynamics (PD). Nevertheless, BP circadian variation has been scarcely included in PK-PD models of antihypertensive medications to date. In this work, we developed PK-PD models that include circadian rhythm to find the optimal dosing time (Ta) of first-line antihypertensive medications for dipper and non-dipper patterns. The parameters of the PK-PD models were estimated using global optimization, and models were selected according to the lowest corrected Akaike information criterion value. Simultaneously, sensitivity and identifiability analysis were performed to determine the relevance of the parameters and establish those that can be estimated. Subsequently, Ta parameters were optimized to maximize the effect on BP average, BP peaks, and sleep-time dip. As a result, all selected models included at least one circadian PK component, and circadian parameters had the highest sensitivity. Furthermore, Ta with which BP>130/80 mmHg and a dip of 10-20% are achieved were proposed when possible. We show that the optimal Ta depends on the therapeutic objective, the medication, and the BP profile. Therefore, our results suggest making chrono-pharmacological recommendations in a personalized way. Author summary Blood pressure (BP) exhibits a circadian rhythm, with a rise during active hours, a small postprandial valley, and a deeper drop during sleep. A low nocturnal decrease in BP is a relevant cardiovascular risk factor, as are the average and peaks of BP in hypertensive patients. Studies have shown that antihypertensive medications' effect varies at different dosing times (Ta). Indeed, hypertension chronotherapy significantly affects long-term cardiovascular risk. Using mathematical modeling, we established that incorporating the circadian rhythm on pharmacokinetic constants allows better prediction of the effect of antihypertensive medicines on BP. In addition, we revealed that the optimal Ta for antihypertensive medications is different when optimizing the nocturnal BP decrease, the average BP reduction, and the average BP peaks reduction, i.e., they are competitive optimization objectives. Moreover, models allowed us to find optimal Ta parameters that achieve the current therapeutic objective (BP<130/80mmHg), and, at the same time, optimal percentages of nocturnal BP decrease for different BP profiles for most antihypertensive medications studied, supporting personalized medicine for hypertension.

Automated summary

Studies have shown that incorporating circadian rhythm into pharmacokinetic models allows for better prediction of the effect of antihypertensive medications on blood pressure. Furthermore, optimizing the timing of medication administration depends on specific therapeutic objectives, the type of medication, and the patient's blood pressure profile. Therefore, personalized chrono-pharmacological recommendations for hypertension treatment are important.