Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16 455) and its enantiomers in healthy male volunteers

• Published in: Biopharmaceutics & drug disposition Vol. 19; no. 7; pp. 455 - 463
• Main Authors: Robbins, Doris K., Castles, Mark A., Pack, David J., Bhargava, Vijay O., Weir, Scott J.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Ltd 01.10.1998; Wiley
• Subjects: achiral; Adult; Area Under Curve; Biological and medical sciences; Chromatography, High Pressure Liquid; Cross-Over Studies; Double-Blind Method; enantiomers; fexofenadine hydrochloride; healthy males; Histamine and antagonists. Allergy; Histamine H1 Antagonists - administration & dosage; Histamine H1 Antagonists - pharmacokinetics; Humans; Male; MDL 16 455; Medical sciences; Middle Aged; pharmacokinetics; Pharmacology. Drug treatments; Spectrometry, Fluorescence; Stereoisomerism; Terfenadine - administration & dosage; Terfenadine - analogs & derivatives; Terfenadine - pharmacokinetics; Human; Single dose; Oral administration; Fexofenadine; Normal; Antihistaminic; Dose activity relation; Multiple dose; Stereoselectivity; Enantiomer; Antagonist; Pharmacokinetics; H1 Histamine receptor
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/(SICI)1099-081X(199810)19:7<455::AID-BDD130>3.0.CO;2-W

The pharmacokinetics and dose proportionality of fexofenadine, a new non‐sedating antihistamine, and its enantiomers were characterized after single and multiple‐dose administration of its hydrochloride salt. A total of 24 healthy male volunteers (31±8 years) received oral doses of 20, 60, 120 and 240 mg fexofenadine HCl in a randomized, complete four‐period cross‐over design. Subjects received a single oral dose on day 1, and multiple oral doses every 12 h on day 3 through the morning on day 7. Treatments were separated by a 14‐day washout period. Serial blood and urine samples were collected for up to 48 h following the first and last doses of fexofenadine HCl. Fexofenadine and its R(+) and S(−) enantiomers were analysed in plasma and urine by validated HPLC methods. Fexofenadine pharmacokinetics were linear across the 20–120 mg dose range, but a small disproportionate increase in area under the plasma concentration–time curve (AUC) (<25%) was observed following the 240 mg dose. Single‐dose pharmacokinetics of fexofenadine were predictive of steady‐state pharmacokinetics. Urinary elimination of fexofenadine played a minor role (10%) in the disposition of this drug. A 63:37 steady‐state ratio of R(+) and S(−) fexofenadine was observed in plasma. This ratio was essentially constant across time and dose. R(+) and S(−) fexofenadine were eliminated into urine in equal rates and quantities. All doses of fexofenadine HCl were well tolerated after single and multiple‐dose administration. © 1998 John Wiley & Sons, Ltd.