OBJECTIVE: A pilot clinical study was conducted to evaluate the toxicity of a single dose of L-asparaginase loaded in red blood cells (RBCs). METHODS: Thirteen patients received a single dose of L-asparaginase in the range 30-200 i.u.kg-1. The enzyme was loaded in one autologous blood unit using a lysis-resealing process. A control population of 33 patients receiving L-asparaginase intravenously were tested in parallel. IgG, IgM and IgE class anti-L-asparaginase antibodies were detected using specific radioimmunoassays. RESULTS: L-Asparaginase pharmacodynamic parameters may be greatly improved by administration of the drug after internalisation in RBCs as compared to intravenous injection of free drug. The drug elimination was prolonged and similar to that of circulating carrier. After one injection of 30 i.u.kg-1, plasma L-asparagine was eliminated in 10 days and this was extended to 50 days for 150-200 i.u.kg-1. The drug was well tolerated and only transient variations were observed for some of the biological parameters measured. We did not reach the maximum tolerable dose (MTD) of L-asparaginase loaded in RBCs. No significant clinical toxicity was detected. In particular, no immune adverse effects were observed. CONCLUSION: This study opens new perspectives for the clinical utilisation of L-asparaginase. This mode of administration of the drug is able to improve pharmacodynamic parameters and enzymic efficacy and to increase the general tolerance of the treatment.
OBJECTIVE: A pilot clinical study was conducted to evaluate the toxicity of a single dose of L-asparaginase loaded in red blood cells (RBCs). METHODS: Thirteen patients received a single dose of L-asparaginase in the range 30-200 i.u.kg-1. The enzyme was loaded in one autologous blood unit using a lysis-resealing process. A control population of 33 patients receiving L-asparaginase intravenously were tested in parallel. IgG, IgM and IgE class anti-L-asparaginase antibodies were detected using specific radioimmunoassays. RESULTS:L-Asparaginase pharmacodynamic parameters may be greatly improved by administration of the drug after internalisation in RBCs as compared to intravenous injection of free drug. The drug elimination was prolonged and similar to that of circulating carrier. After one injection of 30 i.u.kg-1, plasma L-asparagine was eliminated in 10 days and this was extended to 50 days for 150-200 i.u.kg-1. The drug was well tolerated and only transient variations were observed for some of the biological parameters measured. We did not reach the maximum tolerable dose (MTD) of L-asparaginase loaded in RBCs. No significant clinical toxicity was detected. In particular, no immune adverse effects were observed. CONCLUSION: This study opens new perspectives for the clinical utilisation of L-asparaginase. This mode of administration of the drug is able to improve pharmacodynamic parameters and enzymic efficacy and to increase the general tolerance of the treatment.
Authors: Patrick M Glassman; Elizabeth D Hood; Laura T Ferguson; Zongmin Zhao; Don L Siegel; Samir Mitragotri; Jacob S Brenner; Vladimir R Muzykantov Journal: Adv Drug Deliv Rev Date: 2021-09-29 Impact factor: 15.470