Pharmacokinetics, pharmacodynamics, and tolerance of single- and multiple-dose fexofenadine hydrochloride in healthy male volunteers.
BACKGROUND
Fexofenadine is a selective, nonsedating H1-receptor antagonist that relieves symptoms of allergic conditions.


METHODS
Two randomized, double-blind, parallel-group, placebo-controlled dose-escalation studies were performed in healthy men to determine the maximum tolerated oral dose, pharmacokinetics, pharmacodynamics, and safety of fexofenadine hydrochloride. In the first study, 87 subjects (6 in the active drug group and 2 in the placebo group) received single oral doses of fexofenadine hydrochloride ranging from 10 to 800 mg or placebo. In the second study, 32 subjects (3 in the active drug group and 1 in the placebo group) received multiple fexofenadine hydrochloride doses ranging from 20 to 690 mg or placebo twice daily for 28 1/2 days. Serial plasma and urine samples were collected. Fexofenadine concentrations were determined by HPLC and fluorescence. Wheal and flare response to intradermal histamine was used to evaluate antihistaminic activity.


RESULTS
Fexofenadine hydrochloride was rapidly absorbed, reaching peak concentrations in 0.83 to 1.33 hours. Single-dose mean concentration ranged from 46 to 6383 ng/mL, and steady-state maximum plasma concentration ranged from 58 to 4677 ng/mL. Mean area under the plasma concentration-time curve was approximately proportional to dose. Oral clearance, renal clearance, and cumulative percent of drug excreted in urine were similar after single and multiple doses and were generally constant over the dose range studied. Inhibition of skin wheal and flare was shown for single doses of 40 mg and higher and for all multiple doses. No fexofenadine dose-related trends or apparent differences from placebo were found for any safety parameter.


CONCLUSIONS
Fexofenadine hydrochloride was well tolerated at oral doses up to 11 times the recommended therapeutic dose. In addition, fexofenadine hydrochloride showed significant antihistaminic activity and dose-proportional pharmacokinetics over a wide dosing range.
Russell
T
T
Department of Clinical Pharmacokinetics, Hoechst Marion Roussel Inc., Kansas City, MO 64137-1405, USA.
Stoltz
M
M
Weir
S
S
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012044:Regression Analysis; D016593:Terfenadine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D006633:Histamine Antagonists; D016593:Terfenadine; C093230:fexofenadine