Steady state pharmacokinetics of nortriptyline in the frail elderly

The frail elderly, for whom chronic disease and disability are essentially universal, are at high risk for depression and are specifically vulnerable to the adverse effects of antidepressant medication. There have, however, been few investigations of either the pharmacokinetics or the clinical investigations of either the pharmacokinetics or the clinical response to antidepressants in such patients. We report on the pharmacokinetics of nortriptyline at steady state in a group of 22 patients, average age 84, living within an institutional setting. Comparison of our findings with those previously reported for younger and healthier subjects suggests that there are no clinically significant group differences in nortriptyline kinetics. Plasma levels of nortriptyline and those of both the trans- and cishydroxylated metabolites are linear with daily dose. Mean (and SD) for the parameter (plasma level/dose) was 1.21 (0.63) ng/ml/mg/day for the parent compound, 1.41 (0.86) for the trans metabolite, and 0.30 (0.16) for the cis metabolite. There was no significant correlation across individuals between the accumulation of the parent compound and the metabolites. Based upon these data, the average dose of nortriptyline required to achieve a plasma level of 100 ng/ml is 80 mg/day. Dose requirements, however, vary between individuals by a factor of 20. Plasma levels measured 24 hours after a 25-mg test dose of nortriptyline can allow early identification of slow metabolizers. Twenty-four-hour plasma levels (mean 8.8 ng/ml, SD 3.2) were significantly correlated with steady state levels at 25 mg/day (r = 0.71), steady state levels at 50 mg/day (r = 0.73), and each individual's average (plasma level/dose) (r = 0.57).