Albutropin: a growth hormone-albumin fusion with improved pharmacokinetics and pharmacodynamics in rats and monkeys.
Growth hormone (GH) replacement therapy is used to treat GH deficiency. Treatment requires daily administration because of the short plasma t(1/2) of GH. Albutropin, human GH fused at its N-terminus with human serum albumin, should be cleared from the circulation more slowly than GH. Pharmacokinetic and pharmacodynamic studies of albutropin were conducted in rats and monkeys. After subcutaneous (s.c.) dosing in rats, a twofold decrease in clearance and a fourfold increase in plasma half-life were seen with albutropin compared to GH. In monkeys, s.c. administered albutropin (0.3 mg/kg) had a sixfold longer terminal half-life and an eightfold slower clearance than GH (0.3 mg/kg). A single subcutaneous administration of albutropin (0.3, 1.5 and 4 mg/kg) increased plasma insulin-like growth factor 1 (IGF-1) levels for up to 7 days. Seven consecutive daily s.c. injections of GH at 0.3 mg/kg resulted in an increase in IGF-1 equivalent to that induced by a single administration of albutropin at 4 mg/kg. Albutropin (1-20 microg/kg) dosed daily, every other day or every 4 days significantly increased cumulative body weight gain and tibial epiphyseal growth plate width in hypophysectomized rats compared to equimolar doses of GH. These results suggest that albutropin could be given less frequently than GH and achieve therapeutic effects in patients.
Osborn
Blaire L
BL
Human Genome Sciences, Inc., Rockville, MD 20850, USA. Blaire_Osborn@hgsi.com
Sekut
Les
L
Corcoran
Marta
M
Poortman
Carol
C
Sturm
Bonnie
B
Chen
Guoxian
G
Mather
Donald
D
Lin
Hsiu Ling
HL
Parry
Tom J
TJ
D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006132:Growth Plate / Q000187:drug effects / Q000254:growth & development; D019382:Human Growth Hormone / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007016:Hypophysectomy; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D012709:Serum Albumin / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D012737:Sex Factors; D013977:Tibia / Q000187:drug effects / Q000254:growth & development; D013997:Time Factors
D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I