Studies On Toxicology And Toxicokinetics Of YXCK

YXCK is an injectable formulation for the Dexlansoprazole,a proton pump inhibitor.This study was performed via single and repeated dosing of rodents to investigate the response,degree,dose-effect relationship,time-effect relationship,and reversibility of the toxicity,and to determine potential target organs.The TK profiles characterizing were studied to evaluate the relationship between the drug exposure and the toxicological results.The results were provided the referrence for drug research and clinical trials.This study of YXCK is consisted of two part test: the intravenous single-dose toxicity study in ICR mice and 28 days intravenous toxicity and toxicokinetics study in SD rats.There were 5 groups in the single-dose toxicity study,including the vehicle group(0.9%sodium chloride injection),low dose test article group(75 mg/kg),middle dose test article group(100 mg/kg),high dose test article group(150 mg/kg),and Lansoprazole group(150mg/kg)for control.YXCK and Lansoprazole were once injected via tail vein,then observed for 14 days.The ICR mice of 75,100,and 150 mg/kg group appeared toxic symptoms within30 minutes after administration,such as gait instability,prostrate,and disappearance of righting reflex,and then recovered after 4 hours.Some animals of 150 mg/kg YXCK group and Lansoprazole for injection group were found dead within 30 minutes after administration.During the recovery period,edema and scab were found in the injection site,and the severity of irritation was related to the concentration of YXCK.The maximum tolerated dose(MTD)was 100 mg/kg for single bolus injection of YXCK.There was no increase in the toxicity of YXCK in mice compared with the single dose toxicity of Lansoprazole.In the repeated-dose toxicity study,there were 5 groups in the study,including the vehicle control group(0.9% sodium chloride injection),low dose test article group(5 mg/kg),middle dose test article group(15 mg/kg),and high dose test article group(45 mg/kg),and Lansoprazole group(45 mg/kg)for control.The YXCK and Lansoprazole were injected once a day via tail vein for 28 days,and then observed for 28 days.The assessments carried out on the scheduled necropsied main study animals toward the end of the dosing and recovery periods included urinalysis,hematology,coagulation testing and serum chemistry.A panel of tissues/organs were collected and observed.Major organs were weighed and organ-weight ratios were calculated.All tissues of 45 mg/kg and control groups and all gross lesions and target organs from the low-dose and middle-dose groups were examined microscopically.Inthe TK study,TK profile was determined based on the exposure of YXCK and Lansoprazole in blood on D1 and D28.In the 45 mg/kg YXCK group,spontaneous activity decreased and the salivation emerged immediately appeared after administration.With the prolonged administration period,secretions(red)in the nose and/or eyes were observed and in the 45mg/kg group of lansoprazole injection,the spontaneous activity decreased and the salivation emerged immediately after the administration.The tail irritation was found in the 15,45mg/kg group of YXCK and the Lansoprazole group.There were no test article-related changes in body weight,food consumption,urinalysis,hematology,coagulation testing and serum chemistry.At the end of dosing period,decreased absolute and relative weights of thymus were observed at YXCK 5 and 45 mg/kg and the Lansoprazole group,and the thymic cortical atrophy(decrease in cortical lymphocytes)was observed at YXCK 45 mg/kg and the Lansoprazole group,but the changes were considered to be related to the test article and recovered at the end of the recovery period.The study of Toxicokinetics results showed that at YXCK doses of 5 to 45 mg/kg,YXCK exposure increased in proportion to the dose.Continuous administration for 28 days resulted in no accumulation of drugs.There was no gender difference between the exposure of male and female rats.Exposure to Lansoprazole in female rats was higher than in male rats.Based on Dexlansoprazole,the exposure of rats to the first and last dose of YXCK was essentially twice that of the lansoprazole group.SD rats were intravenously injected with 5,15 and 45 mg/kg of YXCK for 28 days,the toxic target organ was thymus;compared with the toxicity of Lansoprazole for injection,the exposure to Dexlansoprazole was nearly 2 times,but there was no increase in toxicity was observed.The maximum tolerated dose(MTD)was 45 mg/kg,and the no-observed effect level(NOEL)was5 mg/kg.