Phamacokinetics of Sustained-release Formulation of Growth Hormone in Experimental Animal / 대한소아내분비학회지

ABSTRACT

PURPOSE:Growth hormone(GH) therapy is very effective for the treatment of short stature, but it is unconvenient that GH should be injected daily because of short half-life. Sustained-release forms of GH preparation is needed for better compliance. This study aimed to measure peak pattern and duration of release of hGH from solid microparticles using sodium hyaluronate. METHODS:In group 1, hGH(EutropinTM) 285microg/kg was injected subcutaneously to 2 Jindo dogs everyday for 7 days. In group 2, hGH solution(EutropinTM) was continuously infused subcutaneously for 12 hours a day for the first 2 days via mini pump(minimed co.) and then for 24 hours a day thereafter until 7th day with the rate of 11.9microg/kg/hr. In group 3, dose of 2mg/kg hGH in sustained-release formulation using sodium hyaluronate, was injected subcutaneously to 3 Jindo dogs. In group 4, two dose levels of 1mg/kg and 2mg/kg hGH in sustained-release formulation using sodium hyaluronate, were injected subcutaneously to each group of 4 Beagle dogs. To evaluate side reactions from continuous injection of sodium hyaluronate, sustained release form of hGH 2mg/kg was injected to 4 Beagle dogs once a week for 4 weeks and compared to 4 control Beagle dogs. Blood samples were withdrawn half- hourly for 6 hour and 2-4 times a day thereafter in Jindo dogs and at 6hr, 12hr, 22hr in the first day and twice a day(at 900, 1600 O'clock) for the following 6 days. RESULTS:In group 1, peak GH conc. of 122+/-27ng/ml was observed at 1 hour after hGH(EutropinTM) 285microg/kg injection and 1/2 of peak GH conc. at 4 hour. and decreased to 2ng/ml at 24 hour. GH AUC(Area under curve) was 670(ng/ml.hr). In group 2, initial steady state GH conc. of 25ng/ml occurred after 6 hour, however, GH conc. decreased gradually to 16ng/ml at the 7th day. GH AUC based on th initial steady state GH conc. was 600(ng/ml.hr). In group 3(Jindo dogs), GH conc. was peaked at 12 hour and 1/2 of peak GH conc at 30-46 hour and decreased to baseline at 70 hour. GH AUC was 2173(ng/ml.hr). In group 4(Beagle dog), peak GH concentrations of 56+/-7ng/ml and 108+/-12ng/ml were observed at 12 hour for the doses of 1mg/ kg and 2mg/kg, respectively and 1/2 of peak GH conc at 48 hour and decreased to baseline at 80 hour. GH AUC was 3560(ng/ml.h) for 2mg/kg treated dogs. Serum IGF-1 was increased to peak levels of 520ng/ml, and 580ng/ml for the doses of 1mg/kg 2mg/kg, respectively, and persisted above the baseline till 120 hour. There was no specific side reaction during experimental period. CONCLUSION: Sustained-release form of hGH with sodium hyaluronate released GH for 70-80 hour with the peak level lower than that resulted from the conventional aqueous formulation of the equivalent dose, and higher concentration IGF-I maintained for 120 hour after injection above baseline. More extensive study is needed to permit for new therapeutic application.