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Twenty-four healthy women received 2.4 mg kg-1 dolasetron mesylate (1.8 mg kg-1 dolasetron base) by a 10 min intravenous administration and by oral administration. Pharmacokinetics of dolasetron and of its active reduced metabolite MDL 74156 were monitored for 48 h in plasma. Urine was collected from 0 to 48 h, blood pressure and heart rate were measured at 0, 0.08, 1, 2, 12, 24, and 36 h, and ECGs were measured at 0, 0.08 (intravenous only), 1, 2, and 36 h after dosing. Dolasetron was widely distributed and rapidly reduced (mean t1/2 = 0.23 h) to MDL 74156 (mean t1/2 = 8.05 and 9.12 h after intravenous and oral administration respectively). MDL 74156 was extensively distributed; between 27 (oral route) and 33% (intravenous route) was eliminated unchanged in urine. Safety assessment showed mild to moderate headache, dizziness, and hot flushes after the intravenous administration and headache, abdominal cramps or pain, and constipation after oral administration. Small and clinically non-significant changes in PR, QRS, and QTc intervals were observed. We conclude that there is no obvious difference in dolasetron pharmacokinetics between healthy women and men and that dolasetron can be used as safely in women as in men.

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for Cmin (mean (SD) = 47 center dot 2 (25 center dot 8) against 39 center dot 6 (21 center dot 1) ng mL-1, p = 0 center dot 038), AUC0-24 (2008 (814) against 1754 (714) ng h mL-1, p = 0 center dot 024), and AUC0-48 (2662 (1244) against 2395 (238) ng h mL-1, p = 0 center dot 034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.

Diltiazem is a calcium antagonist used in angina pectoris and hypertension. There is little information concerning the slow-release (SR) formulation in the literature. The pharmacokinetics of diltiazem SR (120 mg) have been assessed over a 36h period in healthy volunteers after single- (SD) and multiple-dose (MD) administrations. Cmax, AUC0-36, and AUC0-infinity were significantly increased at steady state compared to the extrapolated SD values, suggesting accumulation of the drug. Renal and cardiovascular parameters have also been assessed at intervals of 3-6h during baseline (B) and following single and multiple doses of diltiazem SR. Diuresis over a 24 h period was increased, but not significantly, by the administration of diltiazem SR i.e. 1782 ml (MD) and 1915 ml (SD), versus 1626 ml (B). Natriuresis and creatinine clearance were slightly decreased by diltiazem SR, compared to B values; this might be due to the relatively short period over which steady state was maintained (five days) and the effects of norepinephrine and angiotensine II on renal vasculature and the pharmacokinetics of diltiazem SR. No increase in the systolic blood pressure occurred after the administration of diltiazem SR; diastolic blood pressure and PR interval were decreased and increased respectively by diltiazem SR. These results do not appear to be clinically significant. Finally, no relation was found between the pharmacokinetics and pharmacodynamics of diltiazem. This may be attributed to the absence of clinically significant effects in healthy volunteers, the presence of active metabolites, the pharmacokinetics of the SR formulation and/or the accumulation of the drug at steady state.

Cardizem SR and Bi-Tildiem were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross-over randomized study, we assessed whether these two sustained-release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty-four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high-performance liquid chromatogrpahic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash-out. Pharmacokinetics showed statistically significant (p < 0.01) differences in AUC0-12 with means (+/- SD) of 519.2(+/- 172.8) and 429.6(+/- 147.2) ng h ml-1, AUC0-36 of 835.6(+/- 281.6) and 730.9 (+/- 271.5) ng h ml-1 and Cmax of 89.1(+/- 30.3) and 61.1(+/- 21.2) ng ml-1 for Cardizem SR and Bi-Tildiem, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (+/- SD) change in AUC0-12 of -13.6(+/- 20.8) and +8.4(+/- 31.7) mm Hg h (p = 0.0135) and in AUC0-24 of -33.0(+/- 43.7) and -0.3(+/- 59.2) mm Hg h (p = 0.0463) for Cardizem SR and Bi-Tildiem, respectively. These findings suggest that assessment of efficacy of sustained-release formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.