DOSE PROPORTIONALITY AND COMPARISON OF SINGLE AND MULTIPLE-DOSE PHARMACOKINETICS OF FEXOFENADINE (MDL 16455) AND ITS ENANTIOMERS IN HEALTHYMALE-VOLUNTEERS

The pharmacokinetics and dose proportionality of fexofenadine, a new n on-sedating antihistamine, and its enantiomers were characterized afte r single and multiple-dose administration of its hydrochloride salt. A total of 24 healthy male volunteers (31 +/- 8 years) received oral do ses of 20, 60, 120 and 240 mg fexofenadine HCl in a randomized, comple te 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 mor ning on day 7. Treatments were separated by a 14-day washout period. S erial 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 follow ing the 240 mg dose. Single-dose pharmacokinetics of fexofenadine were predictive of steady-state pharmacokinetics. Urinary elimination of f exofenadine 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 a nd quantities. All doses of fexofenadine HCl were well tolerated after single and multiple-dose administration. (C) 1998 John Wiley & Sons, Ltd.