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A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors

Authors Zhu Z, Qian Z, Yan Z, Zhao C, Wang H, Ying G

Received 18 September 2012

Accepted for publication 6 November 2012

Published 4 January 2013 Volume 2013:8(1) Pages 129—136

DOI https://doi.org/10.2147/IJN.S38271

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Zhongling Zhu,1,4 Zhengzi Qian,2,4 Zhao Yan,1,4 Cuicui Zhao,2,4 Huaqing Wang,2,4 Guoguang Ying3,4

1
Department of Clinical Pharmacology, 2Department of Lymphoma, 3Laboratory of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China; 4Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China

Background: Ursolic acid is a promising anticancer agent. The current study aims to evaluate the single- and multiple-dose pharmacokinetics (PK) as well as the safety of ursolic acid nanoliposomes (UANL) in healthy volunteers and in patients with advanced solid tumors.
Methods: Twenty-four healthy volunteers in the single-dose PK study were divided into three different groups, which received 37, 74, and 98 mg/m2 of UANL. Eight patients in the multiple-dose PK study were administered with 74 mg/m2 of UANL daily for 14 days. The UA plasma concentrations were determined using ultra-performance liquid chromatograph-tandem mass spectrometry.
Results: The plasma concentration profiles of all subjects were characterized by a biexponential decline after infusion. The mean peak plasma concentration (Cmax) increased linearly as a function of the dose (r = 0.999). The mean area under the plasma concentration-time curve (AUC) from 0 to 16 hours also increased proportionally with dose escalation (r = 0.998). However, the clearance was constant over the specific dose interval. In the multiple-dose PK study, the trough and average concentrations remained low. The mean AUC, half-life, Cmax, time to Cmax, and the volume of distribution on the first day were similar to those on the last day. All subjects tolerated the treatments well. Most UANL-associated adverse events varied from mild to moderate.
Conclusions: UANL exhibits relatively linear PK behavior with dose levels from 37 mg/m2 to 98 mg/m2. No drug accumulation was observed with repeated doses of UANL. The intravenous infusion of UANL was well tolerated by healthy volunteers and patients with advanced tumors.

Keywords: ursolic acid, nanoliposomes, pharmacokinetics, solid tumor, ultra-performance liquid chromatography, tandem mass spectrometry

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