title: Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers.
abstract: 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.
authors.affiliation: North America Pharmacokinetics Department, Hoechst Marion Roussel, Inc., Kansas City, MO 64134-0627, USA. doris.robbins-weilert@hmrag.com
authors.forename: D K
authors.initials: DK
authors.lastname: Robbins
authors.forename: M A
authors.initials: MA
authors.lastname: Castles
authors.forename: D J
authors.initials: DJ
authors.lastname: Pack
authors.forename: V O
authors.initials: VO
authors.lastname: Bhargava
authors.forename: S J
authors.initials: SJ
authors.lastname: Weir
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D006634:Histamine H1 Antagonists; D016593:Terfenadine; C093230:fexofenadine