Oral Bioavailability Study of 10 mg Cetirizine Tablets

Nowadays bioequivalence studies are a pivotal part of registration dossiers. These studies measure the bioavailabilities of two (or more) formulations of the same active ingredient. The purpose of the study is to show that the bioavailabilities of the formulations under investigation are equal.


1. Effi Setiawati, Pharm, MSc(1)
2. Arini Setiawati, Pharm, PhD(2)
3. Metta Sinta Sari Wiria, Pharm, MSc(2)
4. Lucia Rat Handayani, Chemist(1)
5. Danang Agung Yunaidi, MD(1)
6. Gunawan Harinanto, Chem(1)

1. PT. Equilab International
    Jl. Utan Kayu No.45 B Jakarta 13120
2. Bagian Farmakologi – FKUI / RSCM
    Jalan Salemba 6, Jakarta

Nowadays bioequivalence studies are a pivotal part of registration dossiers. These studies measure the bioavailabilities of two (or more) formulations of the same active ingredient. The purpose of the study is to show that the bioavailabilities of the formulations under investigation are equal. Based on that conclusion, one may subsequently claim that the therapeutic quality of these formulations is identical. The latter means that both the beneficial and side effects are identical and hence the formulations are interchangeable.

Cetirizine hydrochloride is an orally active and selective H1-receptor antagonist. The chemical name is (±)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid hydrochloride. Cetirizine hydrochloride is a racemic compound with an empirical formula of C12H25ClN2O3.2HCl. It is a white, crystalline powder and water soluble substance. The molecular weight is 461.82 and the chemical structure is shown below:

Cetirizine is an antihistamine; its principal effects are mediated via selective inhibition of peripheral H1 receptors. The antihistaminic activity of cetirizine has been clearly documented in a variety of animal and human models. In-vivo and ex-vivo animal models have shown negligible anticholinergic and antiserotonergic activities.

Cetirizine is indicated for the relief of symptoms associated with seasonal or perennial allergic rhinitis. Symptoms treated effectively include sneezing, rhinorrhea, nasal pruritus, ocular pruritus, tearing, and redness of the eyes. Cetirizine is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria. It significantly reduces the occurrence, severity, and duration of hives and pruritus.

The most common adverse reaction in patients aged 12 years and older that occurred more frequently on cetirizine than placebo was somnolence. The incidence of somnolence associated with cetirizine was dose related, 6% in placebo, 11% at 5 mg, and 14% at 10 mg. Fatigue and dry mouth also appeared to be treatment-related adverse reactions.

Cetirizine was rapidly absorbed with a time to maximum concentration (tmax) of approximately 1 hour after oral administration of tablets, chewable tablets or syrup in adults. When healthy volunteers administered multiple doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/ml was observed. No accumulation was observed. Cetirizine pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no effect on the extent of exposure (AUC) of the cetirizine tablet or chewable tablet, but tmax was delayed by 1.7 hours and  2.8 hours, respectively, and Cmax was decreased by 23% and 37%, respectively in the presence of food.

The objective of the present study was to assess whether the bioavailability of 10 mg cetirizine tablets produced by PT FERRON PAR PHARMACEUTICALS (Histrine®) was equivalent to that produced by the innovator (Ryzen®, PT UCB Pharma).

This study was a randomized, single-blind (investigator blind), cross-over study. The study was conducted in 12 healthy volunteers, male volunteers, aged between 18-55 years, body weight within normal range (BMI = 18-25 kg/m2), and signed the informed consent. Healthy criteria were assessed from the results of physical examination and laboratory values of liver function (alkaline phosphatase, ALT, and bilirubin), renal function (serum creatinine and urinalysis), routine hematology and blood glucose.

Subject with pregnant women, nursing mothers, subjects with known contraindication or hypersensitivity to cetirizine and those with chronic gastrointestinal problems will be excluded. Urinary pregnancy test will be applied to women volunteers just before taking the medicine.

This study was carried out in accordance with the Good Clinical Practice (GCP) standards. Ethical clearance was obtained from the Ethics Committeee, School of Medicine, University of Indonesia.

Based on trial procedure, at 06:00 am subjects were instructed to come to the PT Equilab International after an overnight fast, i.e., they were requested to fast from any food and drinks except mineral water from 21:00 h the night before. A pre-dose pharmacokinetic blood sample was taken.  Blood samples were drawn 10 mL at 0 (control), and 5 mL each at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 8, 12, 18 and 24 hours after drug administration.

Breakfast was provided 4 hours after drug administration. All meals and fluids taken by the subjects should be standardized with regards to the type, the amount and the time of administration during the sampling period. After a week wash-out period, the same procedure was repeated with the alternate drug. Every subject received the study drug as a single oral dose in a fasted condition. The study medication was taken with approx. 200 mL water and swallowed without chewing the tablets

The subjects were under direct medical supervision during the days of administration of ceterizine. The serum concentrations of cetirizine were determined using a fully validated high performance liquid chromatography (HPLC) method with ultraviolet detector and diltiazem as the internal standard.

Pharmacokinetic parameters such as maximum cetirizine level attainable in serum (Cmax), length of time required to reach Cmax (tmax), Area Under the Concentration vs. time Curve from 0 to 24 hours (AUC0-24h), Area Under the concentration vs. time Curve from 0 to infinite (AUC0-∞h), elimination half-life (t1/2) were calculated from the serum concentration of both drug products.

EquivTest version 2.0 (Statistical Solution Ltd., Saugus, MA, USA) was used to calculate the statistical differences of AUCT and Cmax using analysis of variance (ANOVA) after transformation of the data to their logarithmic (ln) values, tmax and t1/2 were tested non-parametrically on the original data using Wilcoxon matched-pairs test.

The means of cetirizine serum concentrations PT FERRON PAR PHARMACEUTICALS product (T) and the reference product (R)  are tabulated in Tables I and are plotted in Figure I.
The mean (SD) of AUCT for the test drug (T) and the reference drug (R) were 2133.99 (772.04) and 2141.71 (657.26) ng.h.mL-1, respectively. The mean (SD) of AUCinf for T and R were 2381.52 (895.69) and 2402.84 (797.78) ng.h.mL-1, respectively. The mean (SD) of Cmax for T and R were 322.73  (126.43) and 332.74 (106.02) ng/mL, respectively. The median (range) of tmax for T and R were 0.5 (0.5 – 1.0) and 0.75 (0.5 – 1.0) h, respectively.  The median (range) of  t1/2  for  T and R were 5.99  (2.83 – 10.76) and 6.52 (3.03 – 12.22) h, respectively. The individual pharmacokinetic parameters (AUCT, AUCinf , Cmax, tmax, and t1/2).

The geometric mean ratio (90% confidence intervals) of the AUCT , AUCinf and Cmax  were 98.74%   (89.72 – 108.68%), 98.38% (88.94 – 108.82%), and 95.39% (87.75 – 103.70%), respectively.

The intra-subject coefficient of variation (% CV) estimated obtained from the ANOVA for the AUCinf and Cmax were 13.60% and 11.27%, respectively. Using the table given by Diletti et al (8), the sample size of 12 volunteers was adequate.

Using the Wilcoxon matched-pairs test from the original data, there were no statistically significant differences found between the two drug products for tmax  and  t1/2 values.  No adverse event was encountered during the trial.

Since the 90% confidence interval of the test/reference AUC-ratio and Cmax-ratio were within the acceptance range for bioequivalence, we conclude that the 10 mg cetirizine tablet produced by  PT FERRON PAR PHARMACEUTICALS (Histrine®) is bioequivalent to that produced by the innovator (Ryzen® tablet).

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2.    Guidelines for Good Clinical Practice. National Agency for Drug and Food Control, Jakarta, 2001.
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       Ireland: Statistical Solutions; 2001.
7.    Meddis R. Statistical  Handbook  for  Non-Statistician. London: McGraw Hill 1975.
8.    Diletti E, Hauschke, Steinijans V W. Sample size determination for bioequivalence assessment by means of
       confidence intervals. Int J Clin Pharm 1991 ; 29(1) : 1-8

-Ami Yahya Prasetya Budi-