Inchoate Clinical Research On Ursolic Acid Liposomes, A Natural Antitumor Drug

Objective: Intravenous ursolic acid liposome （which was abbreviated to UAL） is aclass1new drug according to the National Chemical Drug Registration&Classification applied by Wuhan Liyuanheng Pharmaceutical Technology Co., Ltd.This study has the following objectives:（1） to preliminarily investigate the scientificevaluation methods of the clinical safety and validity of pentacyclic triterpenoids withursolic acid as a representative,（2） to determine the appropriate clinical position forUAL, and （3） to provide objective and scientific data for new drug application to theState Food and Drug Administration. Methods: This study reviewed relatedliterature on triterpenoids and their mechanism of antitumor action. A preliminaryprotocol of the first human clinical trials was constructed based on the preclinicalresearch data of UAL which were provided in the materials applied for registration.The targeted basic-clinical translational research was conducted aimed at some newquestions begging answers by the clinical trial protocols designing. Innovativeevaluation methods were added according to the results of the preclinical translationalresearch. Successively, the following inchoate clinical research and analyses wereexecuted: tolerance and pharmacokinetics trials in human body with a single dosing ofUAL, tolerance and pharmacokinetics trials in human body with multiple dosing ofUAL, and PK-PD relevance analysis. In addition, a preliminary evaluation wasperformed on the clinical benefit of UAL in treating advanced malignant tumorpatients. Results: Bibliographic data show that the mechanisms of action forpentacyclic triterpenoid is compatible with the new strategy for cancer treatmentbecause of its multi-way antitumor features in anti-inflammation, apoptosis promotion,anti-invasion, anti-metastasis, and anti-angiogenesis. However, pentacyclictriterpenoid has less selectivity of tumor targets than small molecular compound andweaker killing effect of cancer cells compared with traditional cytotoxic drugs. Abasic-clinical interim research has revealed the organization distributioncharacteristics of UAL, and confirmed a multi-targeted anti-tumor mechanism ofursolic acid in vivo and in vitro. The abirritation effect of UAL and its ability toprolong the survival time of mice with H₂₂ascites hepatoma were also confirmed.Thus, the entry point of clinical research was found, and hepatotoxicity wasemphasized in the first human trials protocol. The following special indices were also identified: improvement in quality of life of advanced cancer patients, vascularchanges surrounding the tumor, variation metabolism of liposome preparation in vivo,adverse effect, clinical benefit, and PK-PD relevance. Tolerance trials in human bodyusing single and multiple doses of UAL has shown that the dose-limiting toxicity ofsingle dose is liver function damage. The maximum tolerated dose is confirmed to be98mg/m². The tolerability of cancer patients is promising by intravenous infusion for14days with doses of56,74, and98mg/m². The main adverse effects include liverfunction abnormality and gastrointestinal reaction, with a severity of grade I-Ⅱ. andthese effects can be spontaneous remission after withdrawal of UAL. Pharmacokineticresearch has shown that the average half-life of UAL is3.90h to4.59h, and that Cmaxand AUC（0-t）have a positive correlation with the dose （r=0.999and r=0.997,respectively）. The distribution of UAL is in accordance with two-compartment model,and the elimination reveals the first order elimination kinetics. Drug accumulation ofUAL will not occur when a cancer patient was administered with a dose of74mg/m²by continuous infusion for14days （once a day）. There is a correlation between themain adverse effects and the pharmacokinetic parameters of UAL. Thegastrointestinal side effect may be related to accumulative drug concentration,whereas an increase in serum transaminase may be caused by C_maxincreased. Inaddition, an increase in triglyceride may be related to the multi-dosing of UAL.Lesions shrink and symptom alleviation can be observed in some patients after twoweeks of using UAL. Self-evaluation reports show that the the quality of life ofpatients is obviously improved. Thus, the high dosage of UAL is likely to increase therecent remission rate. Conclusion: This study successfully completed the firsthuman trials of UAL and confirmed that the dose for phase Ⅱ clinical trial is98mg/m². Based on the results with a few cases, this study preliminarily revealed theappropriate use of UAL and sensitivity people to UAL in the first clinical trial.