CLINICAL PHARMACOLOGY
Mechanism of Action
Fexofenadine, a metabolite of terfenadine, is an
antihistamine with selective peripheral H1-receptor antagonist
activity. Fexofenadine inhibited antigen-induced bronchospasm
in sensitized guinea pigs and histamine release from peritoneal
mast cells in rats. In laboratory animals, no anticholinergic
or alpha1-adrenergic-receptor blocking effects were observed.
Moreover, no sedative or other central nervous system effects
were observed. Radiolabeled tissue distribution studies
in rats indicated that fexofenadine does not cross the blood-brain
barrier.
Pharmacokinetics
Fexofenadine HCl was rapidly absorbed following
oral administration of a single dose of two 60 mg capsules
to healthy male volunteers with a mean time to maximum plasma
concentration occurring at 2.6 hours postdose. After administration
of a single 60 mg dose as an oral solution to healthy subjects,
the mean plasma concentration was 209 ng/ml. Mean steady-state
peak plasma concentrations of 286 ng/ml were observed when
healthy volunteers were administered multiple doses of fexofenadine
HCl (60 mg oral solution every 12 hours for 10 doses). Fexofenadine
pharmacokinetics were linear for oral doses up to 120 mg
twice daily. Although the absolute bioavailability of fexofenadine
HCl capsules is unknown, the capsules are bioequivalent
to an oral solution. The mean elimination half-life of fexofenadine
was 14.4 hours following administration of 60 mg, twice
daily, to steady-state in normal volunteers.
Human mass balance studies documented a recovery of approximately
80% and 11% of the [14C] fexofenadine HCl dose in the feces
and urine, respectively. Approximately 5% of the total dose
was metabolized. Because the absolute bioavailability of
fexofenadine HCl has not been established, it is unknown
if the fecal component represents unabsorbed drug or the
result of biliary excretion.
The pharmacokinetics of fexofenadine HCl in seasonal allergic
rhinitis patients were similar to those in healthy subjects.
Peak fexofenadine plasma concentrations were similar between
adolescent (12-16 years of age) and adult patients.
Fexofenadine is 60% to 70% bound to plasma proteins, primarily
albumin and a1-acid glycoprotein.
Special Populations
Special population pharmacokinetics (for age and
renal hepatic impairment), obtained after a single dose
of 80 mg fexofenadine HCl, were compared to those from normal
subjects in a separate study of similar design. While subject
weights were relatively uniform between studies, these special
population patients were substantially older than the healthy,
young volunteers. Thus, an age effect may be confounding
the pharmacokinetic differences observed in some of the
special populations.
Effect of Age: In older subjects (³65
years old), peak plasma levels of fexofenadine were 99%
greater than those observed in normal volunteers (<65
years old). Mean elimination half-lives were similar to
those observed in normal volunteers.
Renally Impaired: In patients with mild
(creatinine clearance 41-80 ml/min) to severe (creatinine
clearance 11-40 ml/min) renal impairment, peak plasma levels
of fexofenadine were 87% and 111% greater, respectively,
and mean elimination half-lives were 59% and 72% longer,
respectively, than observed in normal volunteers. Peak plasma
levels in patients on dialysis (creatinine clearance £10
ml/min) were 82% greater and half-life was 31% longer than
observed in normal volunteers. Based on increases in bioavailability
and half-life, a dose of 60 mg once daily is recommended
as the starting dose in patients with decreased renal function
(see DOSAGE AND ADMINISTRATION.)
Hepatically Impaired: The pharmacokinetics
of fexofenadine HCl in patients with hepatic disease did
not differ substantially from that observed in healthy subjects.
Effect of Gender: Across several trials,
no clinically significant gender-related differences were
observed in the pharmacokinetics of fexofenadine.
Pharmacodynamics
Wheal and Flare: Human histamine skin wheal and
flare studies following single and twice daily doses of
20 mg and 40 mg fexofenadine HCl demonstrated that the drug
exhibits an antihistamine effect by 1 hour, achieves maximum
effect at 2-3 hours, and an effect is still seen at 12 hours.
There was no evidence of tolerance to these effects after
28 days of dosing.
Effects on QTc: In dogs, (10 mg/kg/day,
orally for 5 days) and rabbits (10 mg/kg, intravenously
over one hour) fexofenadine did not prolong QTc at plasma
concentrations that were at least 28 and 63 times, respectively,
the therapeutic plasma concentrations in man (based on a
60 mg twice daily fexofenadine HCl dose). No effect was
observed on calcium channel current, delayed K+ channel
current, or action potential duration in guinea pig myocytes,
Na+ current in rat neonatal myocytes, or on the delayed
rectifier K+ channel cloned from human heart at concentrations
up to 1 ´ 10-5 M of fexofenadine. This concentration
was at least 32 times the therapeutic plasma concentration
in man (based on a 60 mg, twice daily fexofenadine HCl dose).
No statistically significant increase in mean QTc interval
compared to placebo was observed in 714 seasonal allergic
rhinitis patients given fexofenadine HCl capsules in doses
of 60 mg to 240 mg twice daily for two weeks or in 40 healthy
volunteers given fexofenadine HCl as an oral solution at
doses up to 400 mg twice daily for 6 days.
CLINICAL STUDIES
In three, 2-week, multi-center, randomized, double-blind,
placebo-controlled trials in patients 12-68 years of age
with seasonal allergic rhinitis (n=1634), fexofenadine HCl
60 mg twice daily significantly reduced total symptom scores
(the sum of the individual scores for sneezing, rhinorrhea,
itchy nose/palate/throat, itchy/watery/red eyes) compared
to placebo. Statistically significant reductions in symptom
scores were observed following the first 60 mg dose, with
the effect maintained throughout the 12 hour interval. In
general, there was no additional reduction in total symptom
scores with higher doses of fexofenadine up to 240 mg twice
daily. Although the number of subjects in some of the subgroups
was small, there were no significant differences in the
effect of fexofenadine HCl across subgroups of patients
defined by gender, age, and race. Onset of action for reduction
in total symptom scores, excluding nasal congestion, was
observed at 60 minutes compared to placebo following a single
60 mg fexofenadine HCl dose administered to patients with
seasonal allergic rhinitis who were exposed to ragweed pollen
in an environmental exposure unit.
|
|
