Download Fexofenadine RVG 35246-7

BIOAVAILABILITY OF FEXOFENADINE*
TABLETS, 120 AND 180 MG
RVG 35246 AND RVG 35247
INTRODUCTION
Fexofenadine, a second generation antihistamine, is a specific selective histamine H1-receptor
antagonist. It is the active carboxylic acid metabolite of terfenadine. Fexofenadine is thought
to provide essentially all the therapeutic benefits of terfenadine while avoiding the serious
cardiotoxic and drug interaction risks of the parent drug, and therefore is considered a
relatively safe alternative to terfenadine.
Upon oral administration, fexofenadine is rapidly absorbed. Peak plasma concentrations are
reached after 1-3 hours. The mean Cmax was 427ng/ml after administration of 120 mg once
daily. Plasma protein binding of fexofenadine is approximately 60-70%. Negligible amounts
are metabolized in the liver and the elimination half life is 11-15 hour after repeated
administration. Fexofenadine is excreted in faeces and urine. Presence of food did not appear
to affect the rate or extent of absorption of fexofenadine.
The objective of the study was to compare the single-dose oral bioavailability of fexofenadine
180 mg (test, T) versus reference (R) product (Telfast 180 mg, Aventis Pharma), in healthy
adults males under fasting conditions. In addition, adverse events were collected throughout
the study.
EXPERIMENTAL PART
This study was conducted in compliance with Good Clinical Practice (GCP).
Forty people were to be enrolled in the study (including 4 standby). Thirty-seven entered the
first period and thirty-five completed all periods and were included in the final analysis.
The study was designed as an open-label, balanced, randomized, two-treatment, twosequence, four-period (replicate design), single-dose, crossover comparative bioequivalence
study. A fasting period of at least 10 hours was established. The study consisted of four
treatments periods. The four periods were separated by a wash-out period of 8 days. In each
treatment period each healthy subject received a single dose (1x180 mg) of the test product or
the reference product, in accordance with the randomisation scheme (TRTR or RTRT). Blood
samples were taken before administration and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0,
8.0, 10.0, 12.0, 24.0, 36.0, 48.0, and 72.0 hours following drug administration, in each of the
four periods. Plasma samples from 35 subjects completing all periods of the study were
analysed.
*
Based on a registration study approved by CBG-MEB
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MEASUREMENTS
The concentration of fexofenadine was analysed in the taken blood samples and the following
pharmacokinetic parameters were determined: Cmax; Tmax; AUC0-t; AUC0-∞ ; t ½; Kel.
The 90% parametric confidence intervals were constructed. Bioequivalence was concluded if
these confidence intervals fell within the range of 80-125% for the difference of means of log
transformed parameters Cmax, AUC0-t and AUC0-∞ .
A mixed effect ANOVA model for two/sided tests for bioequivalence (90% confidence
intervals) of log/transformed Cmax, AUC0-t and AUC0-∞ for test and reference formulations
was used. Ratio analysis of log/transformed Cmax, AUC0-t and AUC0-∞ were done.
RESULTS
Thirty-five healthy volunteers completed the study. The pharmacokinetic parameters are
reflected in Table 1. The mean plasma concentrations of fexofenadine measured after
administration of the test product and reference product are reflected in Figure 1.
The 90% confidence intervals of the mean ratio (test/reference) of log-transformed were
within the acceptance range of 80% to 125% for Cmax, AUC0-t and AUC0-∞ .
No serious adverse events were observed during the conduct of this study.
Table 1 Results of log-transformed PK parameters.
PK parameters
Test
Reference
595.970
616.715
Cmax (ng/ml)
3724.55
3803.23
AUC0-t (ng.h/ml)
4071.31
4117.56
AUC0-∞∞ (ng.h/ml)
Ratio% T/R
96.6
97.9
98.9
90% Confidence Interval
89.90 - 107.46
87.34 - 109.81
88.75 - 110.15
Figure 1 Mean plasma concentrations vs time curve for test and reference formulation (n=35)
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CONCLUSION
Both formulations were well tolerated, with no major side effects and no relevant differences in
safety profiles.
The time concentration profile of fexofenadine was very similar to that of reference product.
Using the evaluation criteria described previously, the parameters Cmax, AUC0-t and AUC0-∞
fulfil the requirements for bioequivalence.
It can be concluded that fexofenadine is bioequivalent to the reference product, in terms of
both extent and rate of absorption.
The results of the study with the 180 mg tablets may be extrapolated to the 120 mg tablets,
because of dose linearity for doses between 40-240 mg twice daily.
Teva Pharmachemie
Medical Department
June 2008
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