Guidelines for the design and conduct of human clinical trials on ingestion-time differences – chronopharmacology and chronotherapy – of hypertension medications

Abstract

Zhao (2021) Guidelines for the design and conduct of human clinical trials on ingestion-time differences -chronopharmacology and chronotherapy -of hypertension medications,

Pharmacogenomics and circadian rhythms as mediators of cardiovascular drug-drug interactions

“…These and other concepts derived from the study of circadian rhythms and drugs (chronopharmacology) provide a novel perspective of administration-time differences in the behavior of cardiovascular and other therapies as well as novel insight into the mechanisms and manifestations of DDI. Therefore, the application of circadian rhythm-based investigative protocols is of critical importance not only to fully understand the PK and PD of single therapies when utilized at different times during the 24 ​h, but also the risk for DDI when several therapies are applied simultaneously ( Hermida et al., 2021a ).…”

“…However, the use of the 24 ​h SBP mean as the parameter for assessing the efficacy of hypertension therapy is improper because the SBP asleep mean and extent of asleep SBP dipping are much more strongly associated with CVD risk. Patients who have the same identical SBP mean can have a substantially different asleep SBP mean and dipping pattern and thus be at very different CVD risk ( Hermida et al., 2021a ). Very recently, the combination of bempedoic acid, ezetimibe, and atorvastatin has been shown to reduce LDL-cholesterol significantly in patients with hypercholesterolemia, based on a randomized phase 2 clinical trial ( Rubino et al., 2021 ).…”

Ingestion-time differences in the pharmacodynamics of hypertension medications: Systematic review of human chronopharmacology trials

“…The differences include enhanced asleep BP reduction, increased sleep-time relative SBP decline with corresponding reduced prevalence of the higher CVD risk non-dipper/riser 24 h BP patterning, decreased incidence of adverse events, and improvement in markers of hypertension-associated target organ pathologyreduced albuminuria and increased GFR of the kidney, plus decreased left ventricular posterior diameter and left ventricular mass of the heartwhen hypertension medications are ingested at bedtime rather than upon-waking. The inability of the very small number of trials to verify advantages of the bedtime/evening treatment strategy is likely explained by deficiencies of their study design and conduct [68]. Most noteworthy is the finding that no single reported randomized trial documents better BP-lowering and other medical benefits, safety, or compliance of the most recommended, but unjustified by medical evidence, upon-waking/morning ingestion-time schedule of currently marketed conventional hypertension medications.…”

“…(vi) Trials by Rahman et al [55] and Poulter et al [67] recruited only treated hypertensive persons whose BP was already substantiated to be controlled according to hypertension guidelines. This approach leads to misleading findings when evaluating ingestion-time-dependent effects of BP-lowering therapies [68]. Indeed, in both studies the mean ABP values were actually higher after both morning and evening treatment than at baseline.…”

“…In addition to the insufficient sample size of both of these neutral trials, the rather low, i.e., normal, baseline "daytime" and "nighttime" SBP/DBP means of the BP-controlled recruited participants, precluded the findings of the somewhat lower "nighttime" SBP mean achieved by evening in comparison to morning dosing attaining statistical significance [55,67]. Beyond BP-lowering efficacy of hypertension medications being markedly associated with pre-treatment ABP level, diminishing with lower (close to or actually normal) baseline ABP, it is judged unethical to change the treatment regimen of any patient whose BP is already safely and properly controlled according to guideline-recommended threshold values [68].…”