Pharmacokinetic studies of recombinant human insulin-like growth factor I (rhIGF-I)/rhIGF-binding protein-3 complex administered to patients with growth hormone insensitivity syndrome.
BACKGROUND
GH insensitivity syndrome (GHIS), Laron syndrome, is characterized by severe short stature, high serum GH levels, and very low serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels associated with a genetic defect of the GH receptor. Recombinant human (rh) IGF-I treatment at doses of 80-120 microg/kg given sc twice daily is effective in promoting growth in these patients. We have investigated a newly developed drug, rhIGF-I/rhIGFBP-3, a 1:1 molar complex of rhIGF-I and rhIGFBP-3.


OBJECTIVE
The objectives of the study were to determine IGF-I pharmacokinetics after the administration of rhIGF-I/rhIGFBP-3 in adolescents with GHIS and to evaluate its safety and tolerability.


METHODS
This was an open-label clinical study.


METHODS
The study was conducted in a general pediatric ward of a university teaching hospital.


METHODS
Four patients (one female and three males; mean age, 14.9 yr; mean height sd score, -4.9) with confirmed molecular diagnosis of GHIS agreed to participate in the study.


METHODS
rhIGF-I/rhIGFBP-3 was administered in a single sc injection at 0.5 and 1.0 mg/kg.dose (equivalent to 100 and 200 microg/kg rhIGF-I) after breakfast with a 2-d interval between doses.


RESULTS
IGF-I levels reached a maximum between 19 +/- 8.3 and 15 +/- 6.2 h for the low and high doses, respectively. The circulating IGF-I levels obtained with the low and high doses were similar, although a discrete dose-dependent increase in circulating IGF-I levels was observed. The IGF-I half-life in four subjects after a dose of 0.5 mg/kg rhIGF-I/rhIGFBP-3 was estimated to be 21+/- 4 h. There were no acute adverse events reported, and all blood glucose measurements were normal.


CONCLUSIONS
These data demonstrated that the rhIGF-I/rhIGFBP-3 complex was effective in increasing levels of circulating total and free IGF-I into the normal range for a 24-h period after a single sc administration in patients with GHIS, and that administration of rhIGF-I/rhIGFBP-3 was safe and well tolerated.
Camacho-Hübner
Cecilia
C
Department of Endocrinology, William Harvey Research Institute, John Vane Science Building, First Floor, Charterhouse Square, London EC1M 6BQ, United Kingdom. c.camacho-hubner@qmul.ac.uk
Rose
Stephen
S
Preece
Michael A
MA
Sleevi
Mark
M
Storr
Helen L
HL
Miraki-Moud
Farideh
F
Minuto
Francesco
F
Frystyk
Jan
J
Rogol
Alan
A
Allan
Geoffrey
G
Sommer
Andreas
A
Savage
Martin O
MO
D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D015992:Body Mass Index; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D019382:Human Growth Hormone / Q000502:physiology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D046150:Laron Syndrome / Q000378:metabolism*; D008297:Male; D015233:Models, Statistical; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D001786:Blood Glucose; D002352:Carrier Proteins; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; C075944:insulin-like growth factor binding protein, acid labile subunit; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II