Comparability of biosimilar romiplostim with originator: Protein characterization, animal pharmacodynamics and pharmacokinetics.

The results of preclinical studies of romiplostim analogue GP40141 are presented. The effect of a cell proliferation, phosphorylation of the TPO receptor and JAK2 phosphorylation were studied in the presence of romiplostim and in the presence of GP40141 in a cell line of mice (Mus musculus) lymphoblasts with stable expression of human TPO receptor 32D-hTPOR clone 63. Binding to the TPO receptor and to the neonatal Fc receptor (FcRn) was examined for both romiplostim and the developed analogue. In Sprague-Dawley rats, the dynamics of platelet count after the administration of romiplostim or GP40141 were determined. The pharmacokinetics of romiplostim and GP40141, as well as the dynamics of platelet count, were studied in cynomolgus monkeys. The serum concentrations of romiplostim were determined using a modified colorimetric enzyme-linked immunosorbent assay (ELISA). The data obtained allow us to assert the similarity of the biological action of Nplate® and GP40141.

Toxicity Patterns of Clinically Relevant Metal Oxide Nanoparticles.

Nanostructured drugs are being approved for clinical use, although there is a serious deficit of systematic studies of these materials. Data on toxicity of nanoparticles (NPs) can vary due to different methods of preparation, size, and shape. We investigated the toxicity against cultured human cells, the acute toxicity in mice, and the influence on conjugative transfer of antibiotic resistance genes of clinically relevant NPs such as TiO2, ZrO2, HfO2, Ta2O5, Fe3O4, and AlOOH. NPs were synthesized as aqueous sols by the same method in aqueous solution, with almost identical size 2-10 nm. None of these NPs was cytotoxic at concentrations compatible with water solubility. Furthermore, TiO2, HfO2, Ta2O5, Fe3O4, and AlOOH were not toxic to mice after oral administration. However, ZrO2 showed rather high toxicity, with LD50 2277.8 mg/kg. Experiments with plasmid transfer between bacteria demonstrated that AlOOH NPs were the most hazardous since this material promoted the emergence of resistance to antibiotics. Thus, although our metal oxide NPs are largely non-toxic, their properties may differ in specific biological situations.