Sub-Acute Oral Toxicity Study and Bioequivalence Study of Selected New Chemical Entities

Abstract

AIM: To assess sub-acute oral toxicity study of Alvimopan dihydrate in Swiss albino mice. Objectives: a) To study adverse effects of the Alvimopan Dihydrate at 3 different doses, b) To determine the dose response for adverse effects and to identify no observable adverse effects level (NOAEL) for Alvimopan Dihydrate, and c) To identify affected organs by exposure to Alvimopan Dihydrate (target organs). MATERIALS & METHODS: Study was done as per schedule Y (Drug and Cosmetics Rules, 2005). Both male and female Swiss albino mice (24 each) were taken and divided into following groups: vehicle control (10ml/kg, corn oil, p.o.), and three different dose group of Alvimopan dihydrate i.e. low (12mg/kg), medium dose (24mg/kg), high dose (120mg/kg). Drug was given orally for 28 days period. During study period, clinical observation, mortality, body weight and feed consumptions were noted. At the end of study, biochemical estimation, hematological estimation, gross lesion analysis, absolute organ weight (vital organs) and histopathological analysis were done. RESULTS: Animal of all dose groups did not show any abnormal clinical signs and survived throughout the study period. Both male and female animals did not show and significance (p<0.05) differences in body weight and feed consumption Except some parameters in hematology data, biochemistry data, and absolute organ weight data of Male and female animals of different dose group did not show significant (p<0.05) differences as compared to vehicle control group except some parameters. And except values of ALT, globulin (Biochemistry), and weight of spleen (Organ), other parameters were in normal laboratory mice data range and not related to treatment. Statistically significant (p<0.05) higher the value of globulin was seen in medium dose group (group III) but not in high dose group, similarly for spleen statistically significant (p<0.005) lower weight was seen in low dose group but not in medium and higher dose groups (group III & IV). While statistically significant (p<0.005) lower value of ALT was seen in higher group (group IV) and was dose dependent but it was marginally than lower limit of normal laboratory mice range data (0.4%) & do not have any clinical significance. Hence these statistical significant (p<0.05) changes were considered as incidental and biological variation instead of adverse effect of drug treatment. Observed gross pathological changes were randomly distributed in all groups. In histopathology analysis, lesions were either observed as single incidence in different dose groups or comparable to vehicle control group. No target organ toxicity was found. CONCLUSION: Based upon above results, Alvimopan dihydrate upto 24mg/kg (P.o.) (5X of human equivalent dose) was found to be safe in both male & female Swiss albino mice. Therefore, NOAEL of Alvimopan dihydrate in 28 days study is 24mg/kg (P.o.).