Tolerability, pharmacokinetics and dose linearity of azelastine hydrochloride in healthy subjects

In a double-blind, randomized, 4-period crossover study, single oral doses of azelastine hydrochloride tablets (A-05610, Allergodil, Radethazin, Azeptin, CAS 79307-93-0) were ingested by 12 healthy volunteers (6 males, 6 females, mean age 25.2 +/- 3.5 years). Dose linearity was demonstrated for 2.2, 4.4, 8.8 and 17.6 mg of azelastine hydrochloride. The values of AUC0-infinity and Cmax increased linear to the dose (means of AUC0-infinity: 47.3, 93.7, 208.0 and 405.90 ng-eq h/ml; means of Cmax: 1.5, 3.3, 6.0 and 12.5 ng-eq/ml), whereas tmax and the terminal half-life of elimination (t1/2 beta) were obviously not influenced by the dose. Mean values over all doses and subjects amounted to 4.6 h (tmax) and 25.5 h (t1/2 beta). Plasma levels showed relatively high inter- and somewhat less intraindividual variations. This is most likely due to a varying degree of enterohepatic circulation resulting from alimentary factors. As for the co-detection of azelastine and the pharmacodynamically active metabolite N-desmethyl-azelastine by the radio-immuno-assay (RIA) used, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds and thus the active principle of the drug. Independently of the dosages administered the overall tolerance proved to be very good. According to this trial the therapeutic range is wide enough to recommend 4.4 mg b.i.d. or single doses of 8.8 mg of azelastine hydrochloride per day for therapy in adult patients.