The Pharmacokinetics and Bioavailability of Clemastine and Phenylpropanolamine in Single‐Component and Combination Formulations

Abstract

Studies were conducted in healthy male volunteers (n = 171; age range, 19-49 years; 22-27 subjects per study) to examine the following: pharmacokinetics 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 clemastine tablets and combination tablets of clemastine and sustained-release phenyl-propanolamine under fasted and fed conditions after single-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 or 12 hours for 7 days per treatment for the steady-state studies. After single oral doses of clemastine solution (1,2, and 4 mg), the area under the concentration-time curve (AUC) and maximum concentration (Cmax) were dose proportional. Clemastine showed a first-pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 +/- 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 +/- 315 L) and low Cmax (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 elimination half-life (t1/2) of clemastine was 21.3 +/- 11.6 hours. Steady-state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1- and 2-mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t1/2 of phenylpropanolamine, but reduced 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 were bioequivalent to the separate components and showed no significant interaction with food.

Clinical pharmacology of clemastine in healthy dogs

“…The plasma kinetic data of clemastine in dogs reveal that the oral bioavailability was low, between 1 and 6%, similar to the 3.4% reported recently to be the oral bioavailability of clemastine in horses 21 . This is considerably lower than the 20–70% estimated for humans 18 . The data are not really comparable as the human data are estimated from oral administration of the drug only, but it can be concluded that one prominent difference between humans, on the one hand, and dogs and horses, on the other hand, is in the uptake and/or first passage metabolism of oral clemastine.…”

“…The data are not really comparable as the human data are estimated from oral administration of the drug only, but it can be concluded that one prominent difference between humans, on the one hand, and dogs and horses, on the other hand, is in the uptake and/or first passage metabolism of oral clemastine. The plasma concentrations obtained in studies of the three species were rather similar although the doses given differed considerably (0.025, 0.2 and 0.5 mg kg −1 , respectively, for humans, horses and dogs, respectively) 18,21 …”

“…Clemastine is also used for hypersensitivity reactions in humans 13,16,17 . Only recently has information on the pharmacokinetics of clemastine in humans been available due to the high potency of the drug and accordingly difficulties in the analysis of drug concentrations in plasma 18 …”

High-performance liquid chromatographic-tandem mass spectrometric method for the determination of clemastine in human plasma

“…Being an ethanolamine derivative it also possesses anticholinergic activity, resulting in a sedative effect. It is administered orally in small doses (2 × 1 mg up to 3 × 2 mg per day) which in turn leads to very low blood levels (C max is around 0.6 ng/ml/1 mg dose) [1]. The lack of sufficiently sensitive analytical methods therefore hindered the extensive study of its pharmacokinetic properties for a long time.…”

“…A recent gas chromatographic method with nitrogen-phosphorous detection was validated having a lower quantitation limit of 0.1 ng/ml [4]. Radioimmunoassay has proven to be selective and sensitive enough to measure pharmacokinetics and bioavailability of clemastine in several studies with 0.1 ng/ml minimum measurable concentration [1].…”