Clinical Pharmacology of GP40321 (Insulin Glulisine Biosimilar): Pharmacokinetic and Pharmacodynamic Comparability in a Hyperinsulinemic-Euglycemic Clamp Procedure.

The aim of the study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T-glu (GP40321, test drug), and reference insulin glulisine in a hyperinsulinemic-euglycemic clamp procedure. During this study, 34 healthy male volunteers underwent the hyperinsulinemic-euglycemic clamp procedure following subcutaneous 0.3 U/kg injection of T-glu or reference insulin glulisine in a randomized, double-blind, crossover study. Plasma glucose levels were monitored every 5 minutes for 8 hours. Glucose infusion rate adjustment was based on the blood glucose measurements. Evaluation of PD was performed using the glucose infusion rate values, while PK was calculated using insulin concentrations measured via enzyme-linked immunosorbent assay. The study results showed that the 90% CI for the geometric mean ratios of primary PK and PD of T-glu and reference insulin glulisine were within 80%-125% comparability limits, and that the safety profiles were comparable. PK, PD, and safety similarity of T-glu and reference insulin glulisine was demonstrated.

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.

Bioequivalence of Reference and Biosimilar Preparations of Premixed Biphasic Insulin Aspart: A Comparative Clamp Study.

Biphasic insulin aspart 30 is a premixed formulation containing a soluble fraction of insulin aspart (30%) and a protamine-crystallized fraction (70%) that was developed to combine the rapid-acting and prolonged advantages of commercially available insulins. The aim of this bioequivalence study was to compare the pharmacokinetics (PKs) of GP-bi-asp and Novo-bi-asp, and evaluate the pharmacodynamic (PD) properties as well as the safety of these drugs in the hyperinsulinemic euglycemic clamp (HEC) procedure. This was a phase 1, randomized, double-blind, 2-sequence, 2-period crossover study. Thirty-four male volunteers who met the inclusion criteria underwent the HEC procedure following a single subcutaneous injection of 0.4 IU/kg of either GP-bi-asp or Novo-bi-asp in the abdomen. After the treatment, the subjects' plasma glucose levels were monitored for 24 hours and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. The PD parameters were calculated using GIR values. Insulin aspart concentrations were measured in blood plasma using validated ELISA assays to evaluate the PK parameters of the investigated drugs. The 90% confidence intervals for the geometric mean ratios of PK (Cins and AUCins-T ) parameters of Gp-bi-asp and Novo-bi-asp were close to 100% and within the 80%-125% limits for establishing bioequivalence. The safety profiles of both drugs were also comparable.

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.

The efficacy and safety of GP40081 (insulin aspart biphasic 30) compared with NovoMix® 30 in Type 2 diabetes patients.

Aim: To evaluate the safety and efficacy of insulin Aspart-Mix biosimilar candidate GP40081 (GP-Asp30) compared with NovoMix® 30 (NN-Asp30). Materials & methods: In a randomized open-label, active-controlled, 26-week non-inferiority clinical trial 264 patients with Type 2 diabetes mellitus were randomized 1:1 to receive once-daily GP-Asp30 or NN-Asp30. The primary safety end point was the immune response rate. Efficacy outcomes were a mean change in HbA1c (primary), frequency of achieving a glycemic g fasting plasma glucose levels, 7-point glucose profiles, and insulin doses. Results: The immune response developed in 10/126 (8%) participants in the GP-Asp30 group and in 10/125 (8%) participants in the NN-Asp30 group (p = 1.000). The mean difference in HbA1c change between groups was 0.12 (95%CI [-0.14, 0.38]). Other secondary efficacy and safety outcomes weren't statistically different between the two groups. Conclusion: GP-Asp30 demonstrated similar safety and efficacy compared with NN-Asp30 and may be considered a biosimilar insulin.

PKPD Modeling and Simulations to Support Biosimilar Development of Biphasic Insulin Aspart 30.

This paper presents an analysis of data from a comparative study of biosimilarity in terms of pharmacokinetics and pharmacodynamics in healthy volunteers using a hyperinsulinemic euglycemic clamp for reference and test biphasic insulin aspart 30 (BIAsp 30). As a result of the study, one of the secondary pharmacodynamic (PD) endpoints did not satisfy the classical criterion of 80%-125% (the lower limit for PD parameter area under the glucose infusion rate-time curve [ AUC GIR 0 - t ${\rm{AUC}}_{{\rm{GIR}}_{0 - {\rm{t}}}}$ ] turned out to be 79.5%). The main hypothesis explaining this result is that the sample size is insufficient to conduct a PD test with 90% statistical power, since the sample size has been calculated based on the coefficient of variation (CV) of pharmacokinetic (PK) parameters. To test this hypothesis, population PKPD (popPKPD) modeling and subsequent simulations of the required number of PD profiles were used. Two popPKPD models were constructed (a one-compartment double simultaneous absorption model for PK and an effect compartment Emax model for PD) to describe the PKPD data of reference and test insulins. As a result, using real data along with model-based simulation data, a biosimilarity test for PD was performed, and the lower limit for AUC GIR 0 - t ${\rm{AUC}}_{{\rm{GIR}}_{0 - {\rm{t}}}}$ became 82.6%, while the CV decreased from 31.7% to 24.1%. Thus, popPKPD modeling and simulations have been shown to be effective in interpreting and supporting the results of clinical biosimilarity trials.

Clinical Pharmacology of Insulin Aspart Biosimilar GP40071: Pharmacokinetic/Pharmacodynamic Comparability in Hyperinsulinemic Euglycemic Clamp Procedure.

Insulin aspart is a short-acting insulin analogue that is used to control postprandial glycemia levels in diabetic patients. The aim of this clinical trial was to compare the pharmacokinetics and pharmacodynamics of GP40071 (GP-Asp) and NovoRapid Penfill (Novo-Asp) in a hyperinsulinemic euglycemic clamp (HEC). This trial was conducted as a part of a GP40071 biosimilar clinical development program. This was a phase I randomized, double-blind, two-period crossover study. Twenty-six healthy male volunteers aged 18 to 45 years who met the inclusion criteria underwent the procedure of an HEC following a single subcutaneous injection of 0.3 IU/kg of either GP-Asp or Novo-Asp into the abdomen. After doses, plasma glucose levels were monitored every 5 minutes for 8 hours. The adjustment of the glucose infusion rate (GIR) was based on the blood glucose measurements. The GIR values were used to evaluate the PD profiles of the studied drugs. Regular blood sampling was performed during the study to obtain sufficient pharmacokinetic data. The 90% confidence intervals for the geometric mean ratios of the pharmacokinetic (AUCins.0-t , Cins.max ) and pharmacodynamic (GIRmax , AUCGIR0-t ) parameters of GP-Asp were within the 80%-125% comparability limits. The safety profiles of the drugs were also comparable. Bioequivalence, similar PD, and safety of GP-Asp and Novo-Asp were demonstrated.

Modeling of Pharmacokinetic Profiles of Insulin Aspart and Biphasic Insulin Aspart 30/70.

This study includes modeling and simulation of insulin aspart pharmacokinetics (PK). The authors used PK data of biosimilar insulins-insulin aspart and biphasic insulin aspart 30/70-to develop a predictive population PK model for the insulins. The model was built via Monolix software, taking into account the weight-based dosing and the dose and body-weight effects on the parameters. The model-based simulations were performed using the R package mlxR for various administered doses and various ratios of insulin aspart forms for a better understanding of the insulin behavior. The optimal model was a 1-compartment model with a combination of zero- and first-order absorptions, with absorption lag for the soluble form of insulin aspart and first-order absorption for the insulin aspart protamine suspension. The assumption of identical behavior of 2 insulins at the distribution and elimination phases was made. The developed PK model was fitted successfully to the experimental data, and all fitted parameters displayed a moderate coefficient of variation. The PK model allows us to predict PK profiles for various doses and formulations of insulin aspart and can be used to improve the accuracy, safety, and ethics of novel clinical trials of insulin.

Safety and efficacy of GP40071 compared with originator insulin aspart (NovoRapid® Penfill®) in Type 1 diabetes mellitus.

Aim: To compare safety and efficacy of GP40071 insulin aspart (GP-Asp) and NovoRapid® (NN-Asp). Materials & methods: This randomized open-label, active-controlled, 26-week non-inferiority Phase III clinical trial enrolled 264 Type 1 diabetes mellitus patients (HbA1c: 7.1-12.0%) randomized 1:1 to once daily GP-Asp (n = 132) or NN-Asp (n = 132). The primary safety end point was immune response at week 26. Results: The groups were similar in frequency of immune response (p = 0.323) and in other safety end points. Mean HbA1c change from baseline was -0.57% for GP-Asp and -0.56% for NN-Asp and did not differ between groups (p = 0.955). Intergroup mean difference of HbA1c level change (95% CI) at week 26 from baseline was 0.00 (-0.26, 0.25) %. Insulin doses, fasting plasma glucose levels and seven-point glucose profiles were similar between groups (p > 0.05). The number of patients experiencing hypoglycemic episodes did not differ between the groups (p = 0.497). Conclusion: GP-Asp demonstrated similar safety and efficacy. Trial registration number: NCT04079413 (ClinicalTrials.gov).

Efficacy and safety of GP40021 insulin lispro biphasic compared with Humalog Mix 25 in Type 2 diabetes mellitus patients.

Aim: To compare safety (immunogenicity) and efficacy of a biosimilar insulin GP-Lis25 and a reference insulin Ly-Lis25 (Humalog Mix 25) in Type 2 diabetes mellitus (T2D) patients. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 210 T2D patients, randomized 1:1 to twice-daily GP-Lis25 or Ly-Lis25. The primary end point was immune response at 26th week. Noninferiority margin for HbA1c was 0.4%. Results: Immune response frequency was similar in GP-Lis25 and Ly-Lis25 groups both at week 12 (p = 0.651) and 26 (p = 0.164). The difference of HbA1c change at week 26 was (95% CI) 0.01 (-0.27-0.28)%. Fasting plasma glucose, seven-point glucose profile and insulin dose were similar between groups. Safety did not differ between groups. Conclusion: GP-Lis25 and Ly-Lis25 demonstrated similar safety and efficacy. ClincalTrials.gov identifier: NCT04023344.

Safety and efficacy of GP40061 compared with originator insulin glargine (Lantus®): a randomized open-label clinical trial.

Aim: To compare safety (immunogenicity) and efficacy of GP40061 insulin glargine (GP-Gla) and Lantus® (Sanofi glargine, Sa-Gla) in people with diabetes mellitus. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 180 Type 1 diabetes mellitus patients (HbA1c 6.5-12.0%), randomized 1:1 to once daily GP-Gla (n = 90) or Sa-Gla (n = 90). The primary end point was immune response at 26th week. Results: The frequency of immune response was similar in GP-Gla and Sa-Gla (p = 1.000). Groups were similar in terms of other safety end points. Mean HbA1c change from baseline was -0.66% for GP-Gla and -0.77% for Sa-Gla, and did not differ between groups (p = 0.326). Insulin doses, fasting plasma glucose and seven-point glucose profiles were similar between groups. Conclusion: GP-Gla and Sa-Gla demonstrated similar safety and efficacy. ClinicalTrials.gov Identifier: NCT04022993.