Population pharmacokinetic, pharmacodynamic and efficacy modeling of SB12 (proposed eculizumab biosimilar) and reference eculizumab

Abstract

Purpose: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships.

Methods: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA).

Results: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid E_max and sigmoid E_max relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients.

Conclusion: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12.

Keywords: Biosimilar; Eculizumab; Paroxysmal nocturnal hemoglobinuria; Population modeling; SB12.

Fig. 1

Basic goodness-of-fit plots of the final pharmacokinetic model for SB12 and reference eculizumab of A all subjects, B healthy subjects, and C paroxysmal nocturnal haemoglobinuria patients. CWRES, conditional weighted residuals

Fig. 2

Basic goodness-of-fit plots of the final pharmacodynamic model for terminal complement activity for SB12 and reference eculizumab of A all subjects, B healthy subjects and C Paroxysmal nocturnal haemoglobinuria patients. CWRES, conditional weighted residuals

Fig. 3

Basic goodness-of-fit plots of the final pharmacokinetic/pharmacodynamic/efficacy model for SB12 and reference eculizumab in paroxysmal nocturnal haemoglobinuria patients, CWRES, conditional weighted residuals

Fig. 4

Visual predictive check plots of the final model for SB12 and reference eculizumab. A, B Final pharmacokinetic model in A healthy subjects and B paroxysmal nocturnal haemoglobinuria patients. C, D Final pharmacodynamic model in C healthy subjects and D paroxysmal nocturnal haemoglobinuria. E Final pharmacokinetic/pharmacodynamic/efficacy model in paroxysmal nocturnal haemoglobinuria patients. The solid red line represents the median observed value (prediction-corrected), and the semi-transparent red field represents a simulation-based 95% confidence intervals for the median. The observed 5% and 95% percentiles are presented with dashed red line, and 95% confidence intervals for each model predicted percentiles are shown as semi-transparent blue field

Fig. 5

Boxplots of inter-individual variability stratified by treatment group in A pharmacokinetic model, ETA1, ETA2 and ETA3 indicate IIV of CL, V_c and V_p, respectively; B pharmacodynamic model for terminal complement activity, ETA1, ETA2 and ETA3 indicate IIV of E₀, I_max and IC₅₀, respectively, and C pharmacokinetic-pharmacodynamic-efficacy model, ETA1, ETA2 and ETA4 indicate IIV of LL0, LMAX and LGAM, respectively. A–C TRTAN indicates treatment group; 1 = SB12, 2 = EU- ECU, 3 = US-ECU