The Influence of Time of Administration on the Pharmacokinetics of a Once-a-Day Diltiazem Formulation: Morning Against Bedtime

Pharmacokinetics of a Novel Diltiazem HCl Extended‐Release Tablet Formulation for Evening Administration

“…The various area under the plasma concentration‐time indices—AUC 0‐t , AUC 0‐∞ , AUC 0‐τ , and AUC 6 a.m.‐12 p.m. —of diltiazem were also greater when the product was administered in the evening compared to morning administration. These observations are in contrast to the observation of lower bioavailability following bedtime administration compared to morning dosing, which was noted with a different diltiazem preparation 24 …”

“…These observations are in contrast to the observation of lower bioavailability following bedtime administration compared to morning dosing, which was noted with a different diltiazem preparation. 24 The apparent half-life of diltiazem, calculated after single-dose administration, was not significantly different between two treatments, therefore indicating that metabolism was not influenced by time of administration. There was less fluctuation in steady-state diltiazem concentrations following evening administration compared to morning.…”

“…22 Several extended-release (ER) formulations of diltiazem HCl have been introduced into the market over the past two decades, and pharmacokinetic characteristics of these products have been widely published. [23][24][25][26][27] To date, no diltiazem formulation has been developed for nighttime use. Recently, an innovative, extended-release formulation of diltiazem HCl that exhibits a unique dissolution profile, with a built-in lag time, was developed for nighttime dosing.…”

“…Serial blood samples (10 mL each for the single-dose study and 7 mL each for the steady-state study) were taken for analysis of plasma diltiazem, desacetyldiltiazem, and N-desmethyldiltiazem. Blood samples were drawn (Vacutainer ® tubes with K 3 EDTA) at 0 (predose), 2, 3, 4, 6, 8, 10,11,12,13,14,15,16,18,20,24,30,36,42, and 48 hours after administration of the study drug in the single-dose study. In the steady-state study, blood samples were harvested at 0 (predose) on days 1, 4, 5, and 6 and on day 7 at 0 (predose), 2, 3, 4, 6,8,10,11,12,13,14,15,16,18,20,22, and 24 hours after administration of the study drug.…”

Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam

“…Cytochrome‐P450 3A (CYP3A), the most important drug metabolizing enzymes subfamily being responsible for metabolizing almost half of the drugs in use today, has been suggested to show a diurnal pattern in its activity. Several drugs predominantly metabolized by CYP3A, such as triazolam, tacrolimus, and several calcium channel blockers have shown varying pharmacokinetic characteristics depending on the time of their administration during the day. A day‐dependent variability has also been suggested for the hepatic CYP3A mediated metabolism of the endogenously formed cortisol .…”