The pharmacokinetic and pharmacodynamic properties and short-term outcome of a novel once-weekly PEGylated recombinant human growth hormone for children with growth hormone deficiency

Abstract

Objectives: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of Y-shape branched PEGylated recombinant human growth hormone (YPEG-rhGH) and evaluate its short-term efficacy and safety in children with growth hormone deficiency (GHD).

Methods: A total of 43 children with GHD from 12 sites in China were enrolled in this randomized, multicenter, active-controlled, double-blind (YPEG-rhGH doses) trial. Patients were randomized 1:1:1:1 to 100, 120, and 140 μg/kg/week of YPEG-rhGH groups and daily rhGH 35 μg/kg/day groups. The treatment lasted 12 weeks. The primary outcome was the area under the curve of the change of insulin-like growth factor-1 (IGF-1). The secondary outcome was the height velocity (HV) increment at week 12.

Results: A dose-dependent response of maximum plasma concentration (Cmax) and area under the concentration-time curves from 0 to 168 hours (AUC0-168h) were observed for YPEG-rhGH. The ratio of Cmax and the ratio of AUC0-168h from the first to the last dosing were 1.09~1.11 and 1.22~1.26 respectively. A YPEG-rhGH dose-dependent increase in area under effect curve (AUEC) of IGF-1 fold change was observed. Model-derived mean IGF-1 SDS was in the normal range for all three YPEG-rhGH doses. At week 12, HV was 7.07, 10.39, 12.27 cm/year, and 11.58 cm/year for YPEG-rhGH 100, 120, and 140 μg/kg/week and daily rhGH respectively. Adherence and safety were consistent with the profile of daily rhGH. No related serious adverse events were reported.

Conclusion: The PK/PD suggests that YPEG-rhGH is suitable for the once-weekly treatment of pediatric GHD. YPEG-rhGH 120 ~ 140 μg/kg/week provides the closest HV increment with similar safety and tolerability compared to daily rhGH 35 μg/kg/day in children with GHD.

Clinical trial registration: ClinicalTrials.gov, identifier [NCT04513171].

Keywords: Y-shape branched PEGylation; clinical trial; growth hormone deficiency; long-acting growth hormone; prepubertal children.

Conflict of interest statement

LS is the president of Xiamen Amoytop Biotech Co., Ltd. RH and WZ are employees of Xiamen Amoytop Biotech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Liang, Zhang, Wei, Du, Zhang, Yang, Zhang, Gong, Li, Song, Xu, He, Zhou, Zheng, Sun and Luo.

Figures

Figure 1

Model-derived PK profiles of YPEG-rhGH (A), Prediction-corrected visual predictive checks (pcVPC) of the YPEG-rhGH concentration. The hollow dots indicated the prediction-corrected YPEG-rhGH concentration. The top dashed line, the middle solid line and the bottom dashed line indicated 10th percentile, median and 90th percentile of prediction-corrected YPEG-rhGH concentrations. The top, middle and bottom area indicated the 95% confidence interval of each line. (B), model-derived PK profiles of YPEG-rhGH in the 12-week treatment period. The hollow dots and solid line indicated the median of YPEG-rhGH concentrations. The shallow area indicated the 5% and 95% confidence intervals predicted by the model. (C), model-derived PK profiles of YPEG-rhGH within one treatment interval after the first and last dosing. The green and pink area indicated the 95% confident interval of YPEG-rhGH concentration after the first and last dosing.

Figure 2

Model-derived PD profiles of YPEG-rhGH (A), Prediction-corrected visual predictive checks (pcVPC) of IGF-1 fold change (IGF-1 FC). The hollow dots indicated the prediction-corrected IGF-1 FC. The top dashed line, the middle solid line and the bottom dashed line indicated 10th percentile, median and 90th percentile of prediction-corrected IGF-1 FC. The top, middle and bottom area indicated the 95% confidence interval of each line. (B), model-derived PK/PD profiles of IGF-1FC. The hollow dots and solid line indicated the medium of IGF-1 FC. The shallow area indicated the 5% and 95% confidence intervals predicted by the model. (C), the model-derived AUC-dose relationship of IGF-1 FC in GHD children. The black solid line and hollow dots indicated the geometric means of AUCIGF-1 FC with YPEG-rhGH. The dashed line indicated the geometric means of AUCIGF-1 FC with daily rhGH.

Figure 3

Model derived profile of IGF-1 SDS. (A), the model-derived pattern of IGF-1 SDS during dose interval of YPEG-rhGH. (B), model-derived PK/PD profiles of IGF-1 SDS. The green and pink area indicated the 95% confident interval of IGF-1 SDS after the first dose and last dose of YPEG-rhGH. The hollow triangles and dots indicated the mean IGF-1 SDS after the first and last dosing of daily rhGH respectively.

Figure 4

HV and HTSDS before and after the treatments. (A), Mean HV at baseline and Week 12. (B), HTSDS at baseline and Week 12. Data are shown as mean ± SD. *p <0.05, ** p <0.01, *** p <0.001.