The Validity And Safety Study On Doxorubicin Hydrochloride Liposome Injection

In this issue, doxorubicin hydrochloride liposome injection is compared with caelyx, the reference preparation from the perspectives of Pharmacodynamics, pharmacokinetics as well as toxicity to verify the conformities of validity, metabolic process and safety and prepare the preclinical pharmacology and toxicity studies of the doxorubicin hydrochloride liposome injection for the clinical test and going public.1 In vivo animal Pharmacodynamic studyThe clinical effects of in vivo anti-human metastatic oophoroma showed that the relative value-added rates of tumor were less than 40 while using 10 and 20 mg·m-2 dose of doxorubicin hydrochloride liposome injection and caelyx. The in vivo tumor suppressor activity of both the two were all of a sort. Therefore, the dosage and administration of caelyx should be referred to while formulating the clinical dosage regimen of the hydrochloride liposome injection.2 Animal pharmacokinetic studyThe results of the plasma concentration-time curve determined after the i.v. administration in Beagle dogs showed that, there was no significant difference of the main pharmacokinetic parameters like the AUC, Cmax and Tmax of doxorubicin while compared with the caelyx. These two preparations were bioequivalent.The results of in vivo tissue distribution test in tumor-bearing mice showed that the tissue distribution of doxorubicin hydrochloride liposome injection and caelyx were consistent. The whole body could be distributed in 1 h after administration. The regular pattern of tissue distribution in 1 h after administration was:kidney>liver >ovary>heart>muscle>stomach>spleen>intestine tenue>cutis>tumor>adipose >lung>brain. These two were bioequivalent.3 Safety studyThe results of the i.v. acute toxicity study in BALB/c mice showed that after the single i.v. administration of the doxorubicin hydrochloride liposome injection and caelyx in mice, the autonomic activities decreased, nuzzle, pilo-erection, listless, fremitus and death were appeared. The LD50 of mice i.v. administrated by doxorubicin hydrochloride liposome injection was 13.283 mg·kg-1 calculated by Bliss while the of LD50 of mice i.v. administrated by caelyx was 13.283 mg·kg-1. These two were consistent.The results of the 3 months i.v. repeated dose toxicity study in Wistar rats showed the toxicities of these two preparations were consistent. The increase of body weight and the food intake were seriously affected by both of the two. After the administration, the autonomic activities decreased, the clothing hair was matt, nuzzle, body twist and hind limb weakness could be observed. Arrest of bone marrow and the reduction of the proportion of WBC and bone marrow image were found during the clinical indicator examination. The liver function was abnormal. The wet weight of thymus, testis and epididymis were reduced. Only the sertoli cells were found in testicular seminiferous tubule during the pathological examination. Spermatogenic cells decreased, and the interstitial proliferation was found.These results indicate that, as the similar preparation referred to the caelyx, the market product aboard, the doxorubicin hydrochloride liposome injection has the consistent pharmacological action, the metabolic process and the in vivo drug safety and it can be treated as a substitute or additional product in clinical use.