A COMPARATIVE-STUDY OF THE STEADY-STATE PHARMACOKINETICS OF IMMEDIATE-RELEASE AND CONTROLLED-RELEASE DILTIAZEM TABLETS

We have studied the controlled-release properties and relative systemi c availabilities of two dosages of the same controlled-release (CR) di ltiazem tablet formulation by comparing them at steady state with thos e of an immediate-release formulation. We measured 24-hour plasma conc entration profiles during 4-day treatments with diltiazem 90 mg CR tab let bd diltiazem 120 mg CR tablet bd, and conventional diltiazem 60 mg immediate-release (IR) tablet tid. The study had a randomized, three- way crossover design. Twelve healthy men (38-52 y) participated. Troug h plasma concentrations were determined on days 3 and 4. The 24-h plas ma concentration-time profiles were assessed after the last morning do se on day 4 of each period. The following steady-state pharmacokinetic values were calculated: the minimum plasma concentration (C-max), the maximum plasma concentration (C-max), the time interval during which the plasma concentration exceeded 75% of C-max (t(75)), the area under the plasma concentration-time curve (AUC(72-96)), the peak-to-trough fluctuation (PTF), and the area-under-the-curve fluctuation (AUCF). St eady state was achieved on day 3. The pharmacokinetics were comparable . For diltiazem CR 90 mg and diltiazem CR 120 mg, AUC(84-96) (night) w as approximately 75% of AUC(72-84) (daytime). The diltiazem plasma con centration increased slowly from about 6 h after the evening dose of b oth CR tablets, resulting in relatively high plasma concentrations in the early morning hours. Only during treatment with diltiazem CR 120 m g were the plasma concentrations of diltiazem maintained above the min imum therapeutic plasma concentration of 50 mu g . l(-1) throughout th e full 24 h. In conclusion, twice-daily treatment with diltiazem CR ta blets can replace thrice-daily treatment with the conventional diltiaz em IR tablet. The early morning rise of the diltiazem plasma concentra tion, which might lead to a lower incidence of ischaemic events, may b e an important clinical advantage of both CR tablets. Because of the m inimum therapeutic plasma concentration of 50 mu g . l(-1), twice-dail y administration of the 120 mg CR tablet may be preferred from a thera peutic point of view. Diltiazem, a benzothiazepine, is a calcium antag onist used in the treatment of angina pectoris and hypertension. The a nti-ischaemic mechanism of diltiazem seems to result from an increase of myocardial oxygen supply and a reduction in myocardial oxygen deman d, respectively by coronary artery dilatation and/or direct and indire ct haemodynamic effects, such as afterload reduction and heart rate de crease (Braunwald 1982). Its therapeutic effect is evident at daily do sages between 180 and 360 mg (Low et al. 1981). After oral administrat ion it is almost completely absorbed from the gastrointestinal tract, but owing to extensive first-pass metabolism, its systemic availabilit y is approximately 40-50 % (Echizen and Eichelbaum 1986). The time to maximum plasma concentrations after oral administration of immediate-r elease formulations is approximately 3 to 4 h. The elimination half-li fe of diltiazem is 3.5-7 h, implying that frequent dosing is required to maintain effective plasma concentrations. Therefore, a controlled-r elease formulation of diltiazem, designed to be taken twice daily, has been developed.