Background Pegylated liposomal (PL) mitomycin-c lipidic prodrug MLP) may be a useful agent in patients with metastatic colo-rectal carcinoma (CRC). We report here on the pharmacokinetics and clinical observations in a phase 1A/B study with PL-MLP. Methods Plasma levels of MLP were examined in 53 CRC patients, who received PL-MLP either as single agent or in combination with capecitabine and/or bevacizumab. MLP was determined by an HPLC-UV assay, and its pharmacokinetics was analyzed by noncompartmental methods. The correlation between clinical and pharmacokinetic parameters was statistically analyzed. Results PL-MLP was well tolerated with a good safety profile as previously reported. Stable Disease was reported in 15/36 (42%) of efficacy-evaluable patients. Median survival of stable disease patients (14.4 months) was significantly longer than of progressive disease patients (6.5 months) and non-evaluable patients (2.3 months). MLP pharmacokinetics was stealth-like with long T½ (~1 day), slow clearance, and small volume of distribution (Vd). The addition of capecitabine and/or bevacizumab did not have any apparent effect on the pharmacokinetics of MLP and clinical outcome. High baseline neutrophil count and CEA level were correlated with faster clearance, and larger Vd. Stable disease patients had longer T½ and slower clearance than other patients. T½ and clearance were significantly correlated with survival. Conclusions PL-MLP treatment results in a substantial rate of disease stabilization in metastatic CRC, and prolonged survival in patients achieving stable disease. The correlation of neutrophil count and CEA level with pharmacokinetic parameters of MLP is an unexpected finding that needs further investigation. The association of long T½ of MLP with stable disease and longer survival is consistent with an improved probability of disease control resulting from enhanced tumor localization of long-circulating liposomes and underscores the relevance of personalized pharmacokinetic evaluation in the use of nanomedicines.
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Calculated for an MLP single dose of 2.5 mg/kg q4weeks and a cumulative MLP dose of 12.5 mg/kg (1 cycle of 2.5 mg/kg and 5 cycles of 2 mg/kg) to an adult patient of 70 kg weight and 170 cm height. Conversion factor: 1 mg MMC = 3.4 mg MLP.
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We are grateful to Frederic and Lisa Deutsch (BioStats Ltd., Maccabim, Israel) for their collaboration in data management and pharmacokinetic analysis, and to Jenny Gorin (Shaare Zedek MC) for her technical help with HPLC analysis of MLP.
This study was funded by Lipomedix Pharmaceuticals Ltd. (Jerusalem, Israel).
Conflict of interest
A. Gabizon is founder, chief scientist and a director of Lipomedix; E. Tahover declares that she has no conflict of interest; T. Golan declares that she has no conflict of interest; R. Geva declares that she has no conflict of interest; R. Perets declares that she has no conflict of interest; Y. Amitay is an employee (scientist) of Lipomedix; H. Shmeeda declares that she has no conflict of interest; P. Ohana is an employee (vice-president) of Lipomedix.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review boards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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Gabizon, A.A., Tahover, E., Golan, T. et al. Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients. Invest New Drugs 38, 1411–1420 (2020). https://doi.org/10.1007/s10637-020-00897-3
- Colo-rectal cancer