Evaluation of toxicity and single-dose pharmacokinetics of intravenous ursolic acid liposomes in healthy adult volunteers and patients with advanced solid tumors.

Abstract

OBJECTIVE:

The purpose of this study was to investigate the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of ursolic acid liposomes (UAL), as a new drug, in healthy adult volunteers and patients with advanced solid tumors.

METHODS:

All subjects received a single-dose of UAL (11, 22, 37, 56, 74, 98, and 130 mg/m(2)) administered as a 4-h intravenous infusion. Toxicity was assessed and plasma samples were analyzed using validated ultra-performance liquid chromatograph/tandem mass spectroscopy method.

RESULTS:

A total of 63 subjects including 4 patients and 35 healthy adult volunteers for toxicity study and 24 healthy adult volunteers for pharmacokinetic study were enrolled in this trial. The DLT was encountered at 74, 98, and 130 mg/m(2), and consisted of hepatotoxicity and diarrhea. Other adverse events included grade 1 nausea, grade 2 abdominal distention, grade 1 microscopic hematuria, grade 2 elevated serum sodium, grade 1 vascular stimulation, and grade 1 skin rash. The MTD was 98 mg/m(2). The single-dose pharmacokinetic parameters revealed a linear relationship between C(max), AUC(0→24 h), or AUC(0→∞) and escalated doses.

CONCLUSIONS:

The clinical data reported for the first time that UAL had manageable toxicities with MTD of 98 mg/m(2). The DLT were hepatotoxicity and diarrhea. Meanwhile, UAL had a linear pharmacokinetic profile. The registration number of this trial is ChiCTR-ONC-12002385.

• Authors: Xian-Huo Wang, Shi-Yong Zhou, Zheng-Zi Qian, Hui-Lai Zhang, Li-Hua Qiu, Zheng Song, Jing Zhao, Ping Wang, Xi-Shan Hao, Hua-Qing Wang
• Journal: Expert opinion on drug metabolism & toxicology (Expert Opin Drug Metab Toxicol) Vol. 9 Issue 2 Pg. 117-25 (Feb 2013) ISSN: 1744-7607 [Electronic] England
• PMID: 23134084 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Liposomes
• Triterpenes

Topics

• Adult
• Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects)
• Chemical and Drug Induced Liver Injury (blood, epidemiology)
• Cohort Studies
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Gastrointestinal Diseases (blood, chemically induced, epidemiology)
• Humans
• Infusions, Intravenous
• Liposomes
• Male
• Middle Aged
• Neoplasms (blood, drug therapy, epidemiology)
• Triterpenes (administration & dosage, adverse effects)
• Young Adult
• Ursolic Acid