TOLERABILITY AND PHARMACOKINETICS OF SINGLE AND MULTIPLE DOSES OF AZELASTINE HYDROCHLORIDE IN ELDERLY VOLUNTEERS

The tolerability and pharmacokinetics of azelastine hydrochloride (CAS 73907-93-0, A-05610) after single and multiple dosing (4.4 mg as tablet, tau = 12 h) were investigated in 14 volunteers (6 female, 8 male) older than 65 years (70 +/- 5 years, mean +/- SD). The medication was administered as tablets in the morning of days 1 and 11, and b.i.d. on days 4 to 10 in a randomized, open-labelled, uncontrolled study. Tolerance proved to be very good. Reported number of adverse events was independent from height of plasma levels measured, which showed pronounced inter- and intraindividual variation. When comparing pharmacokinetic parameters from plasma levels (determined with a radioimmunoassay (RIA)) of the elderly with those of young volunteers (26 +/- 5 years), there is a difference in half lives (t(1/2) elderly vs young: single dose: 38.5 +/- 15.3 h vs 25.0 +/- 5.2 h; multiple dose: 35.5 +/- 16.3 h vs 55.4 +/- 24.9 h), and also after a single dose AUC and after multiple dosing AUC(tau)(ss), t(max)(ss), C-max(ss), C-min(ss) (pre dose levels), and the ratios of accumulation R(max) and R(min) (calculated from C-max(ss)/C-max and C-min(ss)/C-min) are approximately twice as high in elderly as those in young volunteers. The RIA co-detects besides azelastine the pharmacodynamically active metabolite N-demethyl-azelastine and thus, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds, i.e. the ''active principle''. N-Demethylated metabolites are known to have longer half-lives usually than their parent compounds and thus, accumulate in a higher degree during multiple dosing. Therefore, in this context (RIA!) it is discussed that the N-demethyl metabolite dominates the pharmacokinetic parameters in multiple dosing more than after a single dose. The reason that the pharmacokinetic parameters mentioned above (except t(max), t(max)(ss)) in addition are elevated more in the elderly than in young volunteers after single dosing in part and after multiple dosing in general, might be due to the physiological functional decline with aging. Due to this finding patients greater than or equal to 65 years are recommended to start therapy with half the azelastine dosage, i.e. with 2.2 mg (rhinitis) or 4.4 mg (asthma) as a single daily administration in the evening. After 10-14 days according to the clinical picture in cases of no or insufficient action and lack of adverse drug reactions the dose may be increased. From the viewpoint of pharmacokinetics, due to the long terminal half-life of the ''active principle'' in plasma and the good tolerability of azelastine a single oral dose per day in the elderly seems to be justified, and could be taken into account, possibly at a doubled dose level, for the young as well.