Study On The Immunogenicity, Bioactivity And Pharmacokinetics Of PEGylated RhGH

Objective: To study the immunogenicity, Bioactivity and Pharmacokinetics of mono-PEG_20KD-GH modified by mPEG-Propionaldehyde (mPEG-ALD). Methods: Immunize rabbits by mono-PEG_20KD-GH, then determine the serum antibody; And body weight gain tests of hypophysectomized rats were carried out for potency determination; An ELISA method was established for the determination of mono-PEG_20KD-GH in plasma. The pharmacokinetic parameters of PEG_20KD-GH, rhGH and PEG_20KD-GH were compared after sc the three samples to rabbits; The pharmacokinetics parameters of PEG_20KD-GH and rhGH after sc three dosages of PEG_20KD-GH, iv middling dosage of PEG_20KD-GH and sc middling dosage of rhGH. Results: The antibody induced by PEG_20KD-GH was much lower than that induced by rhGH. Injecting PEG_20KD-GH once of a 6-day period was even more effective than injecting rhGH daily. The pharmacokinetics parameters of PEG_20KD-GH after sc to rabbits were: t_1/2β=19.40±2.07h, AUC=5269.13±433.65h·ng/ml, CL=0.07±0.01L/h. The parameters of PEG_20KD-GH after sc to mice of three dosages were: Cmax=910.15±77.7ng/ml, 1916.54±117.1977.7ng/ml, 2702.46±116.41ng/ml, AUC=17013.6±2605.8h.ng/ml, 35466.4±4218.4h·ng/ml, 52261.1±6948.9h·ng/ml t_1/2β=18.29±3.29h, 17.37±2.56h, 16.21±0.64h. The pharmacokinetics parameters of PEG_20KD-GH after iv to mice of middling dosage were: t_1/2β=14.61±0.62h, AUC=42261.5±3754.9h·ng/ml, CL=0.00048±3.85E-05L/h. The pharmacokinetics parameters of rhGH after sc to mice of middling dosage were: t_1/2β=3.35±0.88h, AUC=3738.7±320.9h·ng/ml, CL=0.00536±0.00059L/h. Conclusion: Studies of immunogenicity, Bioactivity and Pharmacokinetics support that the use of PEGylation extends the activity of rhGH which are normally cleared by filtration and provide promising long-acting alternatives to daily rhGH injections.