Antitumor efficacy, pharmacokinetics, and biodistribution of NX 211: A low-clearance liposomal formulation of lurtotecan

Lurtotecan is a clinically active water-soluble camptothecin analogue that has been formulated into a low-clearance unilamellar liposome, NX 211, Comp arative studies between free drug and NX 211 have been performed assessing pharmacokinetics in nude mice, tissue distribution in tumor-bearing mice, a nd antitumor efficacy in xenografts, Compared with lurtotecan, NX 211 demon strated a significant increase in plasma residence time and a subsequent 15 00-fold increase in the plasma area under the drug concentration curve. The volume of distribution was also greatly restricted, suggesting altered tis sue distribution. Evaluation of tissues 24 h after administration of either [C-14]NX 211 Or [C-14]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 st udies, NX 211 produced a consistent 3-fold or greater increase in therapeut ic 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 28-fold increase in log,, ce ll kill, compared with lurtotecan and topotecan, respectively, Together, th ese data demonstrate that NX 211 has significant therapeutic advantage over Lurtotecan and that the improved antitumor activity is consistent with inc reased exposure and enhanced drug delivery to tumor sites.