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

From the Department of Pharmacokinetics and Toxicology (S. Sista, J. C.-K. Lai, O. Eradiri) and the Department of Clinical Development (K. S. Albert), Biovail Technologies, Ltd., 3701 Concorde Parkway, #800, Chantilly, VA 20151-1126.

A novel diltiazem HCl extended-release (ER) tablet formulation was developed for evening administration in the management of angina and hypertension. Pharmacokinetics of the formulation were evaluated to identify variations in morning (7 a.m. or 8 a.m.) versus evening (10 p.m.) drug administration. Single-dose (360 mg) and multiple-dose (360 mg once daily for 7 days), open-label, randomized, two-way crossover studies of the new diltiazem HCl ER tablets were completed in 48 healthy volunteers. Serial plasma samples were collected via direct venipuncture up to 48 hours postdose and analyzed for diltiazem and its two major metabolites by high-performance liquid chromatography (HPLC). The primary parameters used to assess the data were AUC_0-, AUC_0-, AUC_{6 a.m.-12 p.m.}, C_max, and t_max. Statistical comparisons using ANOVA were evaluated after logarithmic transformation of dose-dependent parameters. Diltiazem HCl ER tablets administered in the evening exhibited 17% and 22% greater bioavailability compared to morning administration under single-dose and steady-state conditions, respectively. The two times of drug administration were bioinequivalent in both studies. The evening schedule also provided more than twofold higher plasma diltiazem levels in the critical morning hours, when both blood pressure and the incidence of cardiovascular events are the highest.

Key Words: Diltiazem Hcl • pharmacokinetics • hypertension • evening adminstration • angina

Address for reprints: Suryanarayana Sista, PhD, Department of Pharmacokinetics and Toxicology, Biovail Technologies, Ltd., 3701 Concorde Parkway, #800, Chantilly, VA 20151-1126.

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