Abstract
Purpose : To assess the suitability of beagle dog as an animal model for the evaluation of formulations in bioavailability and bioequivalence studies. Methods : A generic cetirizine 10 mg tablet formulation was compared with another reference formulation using beagle dog as animal model. A crossover oral comparative bioavailability study was conducted on cetirizine tablet 10 mg in healthy, male dogs under fasting conditions. The formulations were administered orally with the aid of water. Serial blood samples were collected from pre-dose to 48.0 h post-dose and plasma concentrations of cetirizine were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method. Pharmacokinetic parameters were calculated using non-compartmental analysis while bioavailability was assessed using an analysis of variance (ANOVA) model for humans and dogs. Results : Cetirizine plasma concentrations in dog were comparatively higher, in relation to human plasma concentrations, due to the smaller blood volume in former. There was a delay in time to reach maximum plasma concentration (T max ) in dog. Cetirizine formulations were found to be bioequivalent in either of the species (dog and human). The ratio (test\reference) of least-squares mean for area under plasma concentration curve from time zero to last detectable concentration (AUC 0-t ), area under plasma concentration curve extrapolated to infinity (AUC 0-‡ ) and maximum plasma concentration (C max ), calculated for the dogs were comparable to those for humans. AUC 0-t , AUC 0-‡ and C max ratios ranged within 92.81 - 106.80 % for dogs and 95.43 . 104.84 % for humans Conclusion : The results suggest that beagle dogs can be used in place of humans in bioequivalence tests on generic products of cetirizine. Keywords : Cetirizine, Beagle dog, Bioavailability, Bioequivalence, Pharmacokinetics, Noncompartmental
Highlights
Cetirizine is a selective H1 receptor inverse agonist used in the treatment of allergies, hay fever, angioedema, and urticaria
The current study was planned to evaluate suitability of using beagle dog as an animal model to screen out the prototype under development closer to reference product in terms of bioavailability
The AUC extrapolated observed was < 20 % in all cases expect one, which implies that the sampling scheme was adequate for characterization of pharmacokinetic profile
Summary
Cetirizine is a selective H1 receptor inverse agonist used in the treatment of allergies, hay fever, angioedema, and urticaria. To make cost effective formulation, initial development of formulations can be feasible using animal model. This can serve as guideline for planning clinical bioequivalence studies. The current study was planned to evaluate suitability of using beagle dog as an animal model to screen out the prototype under development closer to reference product in terms of bioavailability. This provides an additional advantage in terms of cost benefit, faster execution of study and it would results in faster formulation development process. Kevin et al performed bioavailability studies for ritonavir formulations in which 12 out of 16 experimental ritonavir formulations in dog mirrored those obtained in human (both bioequivalent and nonbioequivalent results) [4]
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