Population Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim Biosimilar GP40141 and Reference Product in Healthy Volunteers to Evaluate Biosimilarity.

GP40141 is a romiplostim biosimilar. A Phase 1 clinical trial was previously conducted in healthy volunteers to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of GP40141 compared to the reference romiplostim (NCT05652595). Using noncompartmental analysis, the biosimilarity of PD end points was determined according to the classical criterion (0.8-1.25). PK end points were also in good agreement between GP40141 and the reference romiplostim; however, the confidence interval for the area under concentration-time curve from time 0 to the time of last measurement was slightly out of the bioequivalence range (0.91-1.29). Population PK/PD was used in the present study to characterize the individual PK and PD data of 56 healthy subjects in 2 cross-over periods of the Phase 1 clinical trial. Body weight and neutralizing antibodies to romiplostim were found to be important predictors of apparent volume of distribution and linear elimination constant, respectively. Within the framework of the conducted modeling, population estimates of PK/PD parameters were obtained, which were in agreement with literature data for the reference romiplostim. Additionally, values of intersubject variability, previously unreported for romiplostim in a healthy subject population, were derived. Covariate analysis, conducted during model development, as well as visual diagnostics and model-based simulations, demonstrated the absence of significant differences in PK and PD between GP40141 and romiplostim-ref.

A randomized, double-blind, comparative study of the pharmacodynamics and pharmacokinetics of GP40141 (romiplostim biosimilar) and reference romiplostim in healthy male volunteers.

AIMS: The pharmacodynamic (PD) similarity between GP40141, a proposed romiplostim biosimilar, and reference romiplostim was evaluated. Pharmacokinetics and safety were also assessed. METHODS: In this phase 1, randomized, double-blind, single-dose, crossover comparative study with an adaptive design, 56 healthy male volunteers were randomized 1:1 to receive a 3 ug × kg-1 subcutaneous dose of GP40141 and reference romiplostim. The PD similarity between GP40141 and the reference romiplostim was determined using the standard equivalence criteria (80%-125%) for the area under the platelet count-time curve from time 0 to the time of the last sampling for PD (AUCplt ) and the maximum observed platelet count (Pmax ). RESULTS: GP40141 and the reference romiplostim exhibited similar PD profiles. 90% CI for the geometric mean ratios for the primary PD parameters (AUCplt, Pmax ) for GP40141 (T) and the reference romiplostim (R) were fully contained within the predefined equivalence limits of 80%-125%: 98.13%-102.42% for AUCplt and 97.56%-105.80% for Pmax . The pharmacokinetic profiles of GP40141 and the reference romiplostim were well described. No adverse events were observed during the clinical trial after the administration of GP40141 and the reference romiplostim. CONCLUSION: This study demonstrates the PD similarity of GP40141 to the reference romiplostim. Both treatments had comparable safety profiles (NCT05652595).

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.