THE PHARMACOKINETICS AND BIOAVAILABILITY OF CLEMASTINE AND PHENYLPROPANOLAMINE IN SINGLE-COMPONENT AND COMBINATION FORMULATIONS

Studies were conducted in healthy male volunteers (n = 171; age range, 19-49 years; 22-27 subjects per study) to examine the following: phar macokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of c lemastine tablets and combination tablets of clemastine and sustained- release phenylpropanolamine under fasted and fed conditions after sing le-dose administration and at steady state, All studies used crossover designs, with randomized drug treatments separated by a 7-day washout period for the single-dose studies, and with administration every 6 o r 12 hours for 7 days per treatment for the steady-state studies, Afte r single oral doses of clemastine solution (1, 2, and 4 mg), the area under the concentration-time curve (AUC) and maximum concentration (C- max) were dose proportional, Clemastine showed a first-pass reduction in the extent of absorption, with oral bioavailability calculated as 3 9.2 +/- 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 +/- 315 L) and low C-max (0.577 +/- 0.252 ng/mL/mg) observed at 4.77 +/- 2.26 hours after administration, and by the biphasic decline in plasma concentration, The terminal elim ination half-life (t(1/2)) of clemastine was 21.3 +/- 11.6 hours. Stea dy-state concentrations of clemastine were consistent with linear phar macokinetic processes, and clearance was unaffected by age in the rang e studied, or by race. Clemastine solution and tablets were bioequival ent, and food had no significant effect on rate and extent of absorpti on of clemastine, The 1- and 2-mg clemastine tablets showed proportion al bioavailability, Coadministration of clemastine with phenylpropanol amine did not significantly influence the pharmacokinetics of clemasti ne or the AUC and elimination t(1/2) of phenylpropanolamine, but reduc ed the rate of absorption of phenylpropanolamine, Combination tablets containing 1 mg or 2 mg of immediate-release clemastine plus 75 mg of sustained-release phenylpropanolamine for twice daily administration w ere bioequivalent to the separate components and showed no significant interaction with food.