Antitumor Efficacy, Pharmacokinetics, and Biodistribution of NX 211: A Low-Clearance Liposomal Formulation of Lurtotecan
2000
Lurtotecan
is a clinically active water-soluble camptothecin analogue that has
been formulated into a low-clearance unilamellar liposome, NX 211.
Comparative studies between free drug and NX 211 have been performed
assessing pharmacokinetics in nude mice, tissue distribution in
tumor-bearing mice, and antitumor efficacy in xenografts. Compared with
lurtotecan, NX 211 demonstrated a significant increase in plasma
residence time and a subsequent 1500-fold increase in the plasma area
under the drug concentration curve. The volume of distribution was also
greatly restricted, suggesting altered tissue distribution. Evaluation
of tissues 24 h after administration of either[
14 C]NX 211 or [ 14 C]lurtotecan to
ES-2 tumor-bearing mice demonstrated a 40-fold increase in radiolabeled
compound in the tumors of NX 211-treated mice compared with mice
treated with lurtotecan. In single-dose efficacy studies, NX 211
produced a consistent 3-fold or greater increase in therapeutic index
compared with lurtotecan in both the KB and ES-2 xenograft models. When
compared at equitoxic levels in repeat-dose efficacy studies, NX 211
generated durable cures lasting >60 days and a 2–8-fold increase in
log 10 cell kill, compared with lurtotecan and topotecan,
respectively. Together, these data demonstrate that NX 211 has
significant therapeutic advantage over lurtotecan and that the improved
antitumor activity is consistent with increased exposure and enhanced
drug delivery to tumor sites.
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