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 (t1/2 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 AUCss tau, tssmax, Cssmax, Cssmin (pre dose levels), and the ratios of accumulation Rmax and Rmin (calculated from Cssmax/Cmax and Cssmin/Cmin) 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.(ABSTRACT TRUNCATED AT 250 WORDS)