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 rel ease diltiazem Mono-Tildiem LP 300 mg was investigated in 12 middle-ag ed (40 - 64 years), 12 elderly (65 - 80 years) patients and compared t o a control group of 54 young healthy volunteers (18 - 36 years). Each subject received daily a single dose of diltiazem slow release (300 m g) in the morning for 5 consecutive days. On the fifth day of treatmen t, the pharmacokinetic parameters of diltiazem and of 2 of its circula ting metabolites (N-monodemethyldiltiazem and deacetyldiltiazem) were evaluated. The mean diltiazem C-max 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 yo ung healthy subjects, respectively. Mean plasma C-min concentration wa s also higher in elderly subjects than in middle-aged and young subjec ts: 129.7 +/- 77.9 ng/ml versus 66.8 +/- 56.8 and 66.3 +/- 32.3 ng/ml, respectively. The AUC(0-24) 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 youn ger people. No statistical difference was observed between young volun teers and middle-aged patients. The T-max 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 elde rly people (> 65 y) the bioavailability of diltiazem is increased, pro bably due to a reduction of the first-pass effect. Based on the pharma cokinetic results, although safety data did not show any specific tren d with age, a precautionary reduction of the dose at the start of the treatment seems advisable.