Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (1998) 64, 612–621; doi:
Pharmacokinetics, pharmacodynamics, and tolerance of single- and multiple-dose fexofenadine hydrochloride in healthy male volunteers
Tanya Russell PhD1, Maxine Stoltz PhD1 and Scott Weir PharmD, PhD1
1Department of Clinical Pharmacokinetics, Hoechst Marion Roussel Inc. Kansas City, Mo, USA
Correspondence: Tanya Russell, PhD, Clinical Pharmacokinetics, Hoechst Marion Roussel, Inc, 10236 Marion Park Drive, F4-M3112, Kansas City, MO 64137-1405.
Received 4 May 1998; Accepted 19 August 1998.
Abstract
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 28½ 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.
