Multicenter studies on the pharmacokinetic profile of sustained-release oral diltiazem (300 mg) after once a day repeated administration: influence of age.

The influence of age on the pharmacokinetics of the oral sustained release diltiazem Mono-Tildiem LP 300 mg was investigated in 12 middle-aged (40-64 years), 12 elderly (65-80 years) patients and compared to a control group of 54 young healthy volunteers (18-36 years). Each subject received daily a single dose of diltiazem slow release (300 mg) in the morning for 5 consecutive days. On the fifth day of treatment, the pharmacokinetic parameters of diltiazem and of 2 of its circulating metabolites (N-monodemethyldiltiazem and deacetyldiltiazem) were evaluated. The mean diltiazem Cmax was 199.3 +/- 117.8 ng/ml, 254.8 +/- 85.2 ng/ml and 154.5 +/- 63.2 ng/ml in middle-aged, elderly, and young healthy subjects, respectively. Mean plasma Cmin concentration was also higher in elderly subjects than in middle-aged and young subjects: 129.7 +/- 77.9 ng/ml versus 66.8 +/- 56.8 and 66.3 +/- 32.3 ng/ml, respectively. The AUC0-24 showed the same trend: 4,042 +/- 1,136 ng/ml.h in elderly, 2,995 +/- 1,905 ng/ml.h in middle-aged, and 2,564 +/- 1,205 ng/ml.h in young subjects. These parameters were statistically higher (p < 0.01) in the elderly subjects than those obtained in younger people. No statistical difference was observed between young volunteers and middle-aged patients. The Tmax did not differ significantly with age (5.1 +/- 4.4, 6.8 +/- 2.8, 6.1 +/- 3.5 hours, respectively). The ratios between the AUC of each metabolite and that of the parent compound did not vary with the age. These results suggest that in elderly people (> 65 y) the bioavailability of diltiazem is increased, probably due to a reduction of the first-pass effect. Based on the pharmacokinetic results, although safety data did not show any specific trend with age, a precautionary reduction of the dose at the start of the treatment seems advisable.