GSK Medicine: Levocetirizine
Study Number: LOC116459
Title: Pharmacokinetic Study of Levocetirizine Oral Solution
-An open-label, randomized, cross-over study to evaluate the pharmacokinetics, the safety and tolerability of
levocetirizine oral solution (5 mg) and cetirizine dry syrup (10 mg), following a single dose in Japanese healthy male
subjectsRationale: Levocetirizine is available only as 5 mg oral tablet in Japan. In the case of pediatric patients aged from 7 to
15 years old, patients need to divide levocetirizine 5 mg oral tablet into halves. Therefore development of new
formulation is desired, such as oral solution and dry syrup (DS). In addition, GSK has been requested to develop new
formulation of levocetirizine for pediatric patients by Japan Pharmaceutical Association. Thus, in Japan, a new
formulation of levocetirizine will be developed, and the primary objective of this study was to compare the oral
bioavailability of levocetirizine when given as levocetirizine oral solution 5 mg or cetirizine DS 10 mg in Japanese
healthy male subjects.
Phase: I
Study Period: 2 May 2012 – 10 Jun 2012
Study Design: This was a single center, open-label, single dose (under the fasted condition), randomized and 2-way
crossover study to evaluate the pharmacokinetics, the safety and tolerability of levocetirizine oral solution 5 mg and
cetirizine DS 10 mg in Japanese healthy male subjects. Each subject received one administration each of
levocetirizine oral solution 5 mg and cetirizine DS 10 mg. There was a washout period of 7 days between study
periods. Subjects returned to the unit 7 days after the dose in period 2 for follow-up assessment.
Centres: This study was conducted at one centre in Japan.
Indication: Allergic rhinitis, Urticaria, eczema/dermatitis, prurigo, and cutaneous pruritus
Treatment: Subjects were assigned to Group A or Group B in accordance with the randomization schedule.
Group
Period 1
Period 2
A (n=10)
B (n=10)
Levocetirizine oral solution 5 mg
Cetirizine DS 10 mg
Cetirizine DS 10 mg
Levocetirizine oral solution 5 mg
Objectives: To demonstrate the bioequivalence of levocetirizine in plasma, when given as a single dose of
levocetirizine oral solution 5 mg, relative to cetirizine DS 10 mg in Japanese healthy male subjects.
Primary Outcome Variable(s): AUC(0-48) and Cmax of levocetirizine after single dose of levocetirizine oral solution
5 mg and cetirizine DS 10 mg under the fasted condition.
Secondary Outcome Variable(s): Safety: Adverse events, changes in clinical laboratory test, vital signs, weight and
12-lead ECG. Pharmacokinetic parameters of levocetirizine: AUC(0-24), AUC(0-t), AUC(0-∞), tmax, t1/2, %AUCex,
CL/F, Vz/F, kel, MRT, and correlation coefficient between time and log concentration of levocetirizine for the points
used in the estimation of kel.
Statistical Methods:
Analysis populations:
The safety population was defined as all subjects who received at least one dose of investigational products. The
pharmacokinetic (PK) population was defined as all subjects with PK samples adequate for the calculation of PK
parameters.
Pharmacokinetics analyses:
Plasma concentrations of levocetirizine at each assessment point were listed to prepare figures showing individual
concentration-time profiles on both linear and semi-log scales.
Plasma levocetirizine concentration-time data was analyzed by non-compartmental method. From the plasma
concentration-time data, the following pharmacokinetic parameters were determined, as data permitted: the maximum
drug concentration in plasma (Cmax), area under drug concentration in plasma-time curves [AUC(0-∞), AUC(0-24),
AUC(0-48) and AUC(0-t)], time to the maximum drug concentration in plasma (tmax), terminal phase half-life (t1/2),
percentage of AUC(0-∞) obtained by extrapolation (%AUCex), apparent clearance following oral dosing (CL/F),
apparent volume of distribution after oral administration (Vz/F), elimination rate constant (kel), correlation coefficient
between time and log concentration of levocetirizine for the points used in the estimation of kel, and mean residence
time (MRT). For each of the derived levocetirizine pharmacokinetic parameters, except tmax, the following summary
statistics were calculated by treatment: the number of subjects, median, minimum, maximum, arithmetic mean, 95%
confidence interval (CI) for the arithmetic mean, standard deviation, coefficient of variation, geometric mean, 95% CI
for the geometric mean and standard deviation of logarithmically transformed data. For tmax, the number of subjects,
median, minimum, maximum, arithmetic mean, 95% CI for the arithmetic mean and standard deviation were
calculated.
Evaluation of bioequivalence was performed according to Guideline for Bioequivalence Studies of Generic Products.
After loge-transformation, AUC(0-48) and Cmax of levocetirizine given as levocetirizine oral solution 5 mg or when
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given as cetirizine DS 10 mg were analyzed separately by analysis of variance (ANOVA). Point estimates and
associated 90% CIs for the difference of two regimens [logμtest-logμref] were constructed using the residual variance,
where μtest and μref were the geometric mean of the levocetirizine oral solution 5 mg and that of cetirizine DS 10 mg,
respectively. These estimate values were then exponentially back-transformed to provide point estimates and
associated 90% CIs for the geometric mean ratio [μtest/μref]. Two regimens were considered to be bioequivalent, if the
90% CIs of the geometric mean ratio of AUC(0-48) and Cmax were within the acceptable range “0.80 - 1.25”.
Safety analyses:
Safety data (adverse events, clinical laboratory evaluation, vital signs, and 12-lead ECG) were presented in tabular
format and summarized descriptively by treatment according to GSK’s Integrated Data Standards Library (IDSL)
standards.
Study Population: Japanese healthy males aged 20-55 years with body mass index (BMI) of the range 18.5-25.0
kg/m2.
Number of Subjects
Planned, N:
20
Randomized, N:
20
Safety population, n (%):
20 (100)
PK population, n (%):
20 (100)
Completed, n (%):
20 (100)
Total Number Subjects Withdrawn, n (%):
0
Demographics
N
20
Females: Males
0:20
Mean Age, years (SD)
28.7 (8.07)
Mean BMI, kg/m2 (SD)
21.61 (1.863)
Mean Height, cm (SD)
171.83 (5.435)
Mean Weight, kg (SD)
63.87 (7.060)
Ethnicity, n (%)
Not Hispanic or Latino:
20 (100)
Race, n (%)
Asian – Japanese Heritage:
20 (100)
Primary Outcome Results:
The ratios and 90% CIs of the geometric least squares (LS) mean levocetirizine Cmax and AUC(0-48) values are
shown below;
Geometric LS mean
Ratioa) of
Pharmacokinetic
N
geometric LS
90% CI of ratioa)
Levocetirizine
Cetirizine DS
parameter
mean
oral solution 5 mg
10 mg
Cmax (ng/mL)
20
199.57
194.27
1.0272
0.9677-1.0905
AUC(0-48) (hr*ng/mL)
20
1791.58
1692.55
1.0585
1.0239-1.0943
a) Ratio = Geometric LS mean of levocetirizine oral solution 5 mg / Geometric LS mean of cetirizine DS 10 mg
Secondary Outcome Results:
Selected plasma pharmacokinetic parameters are summarized below;
Cmax
tmax
AUC(0-48)
AUC(0-∞)
t1/2
Treatment
N
(ng/mL)
(hr)
(hr*ng/mL)
(hr*ng/mL)
(hr)
Levocetirizine
203.3
0.7500
1814.9
1844.7
7.905
20
oral solution 5 mg
(42.49)
(0.500-1.500)
(304.22)
(317.56)
(0.9970)
Cetirizine DS
196.5
1.0000
1710.5
1737.1
7.853
20
10 mg
(31.31)
(0.500-1.500)
(263.31)
(278.99)
(0.9999)
All parameter reported as arithmetic mean (SD) except for tmax which is reported as median (range)
Safety Results:
There were no adverse events in this study.
Serious Adverse Events, n (%):
No non-fatal or fatal SAEs were reported during the study.
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Conclusion:
- Twenty subjects were enrolled in this study and all subjects completed this clinical trial as scheduled.
- Similar plasma concentration profiles of levocetirizine were observed after single doses of levocetirizine oral solution
5 mg and cetirizine DS 10mg under the fasted condition.
- Levocetirizine oral solution 5 mg and cetirizine DS 10 mg were rapidly absorbed following single dose administration
with a median levocetirizine tmax values 0.75 hour and 1.00 hour, respectively. The terminal phase half-life of
levocetirizine oral solution 5 mg and cetirizine DS 10 mg were 7.91 hours and 7.85 hours, respectively.
- The 90% CIs of the geometric mean ratio of AUC(0-48) and Cmax were 1.0239-1.0943 and 0.9677-1.0905,
respectively. Thus, 90% CIs of the geometric mean ratios of AUC(0-48) and Cmax were within “0.80 - 1.25”.
- It was judged that levocetirizine exposure in plasma was equivalent following administration of levocetirizine oral
solution 5 mg and cetirizine DS 10 mg.
- The safety and tolerability of levocetirizine were confirmed following single oral administrations, under the fasted
condition, of levocetirizine oral solution 5 mg and cetirizine DS 10 mg.
- No AEs, SAEs, deaths or withdrawals were reported during the study.
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