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

• Published in: The journal of clinical endocrinology and metabolism 2006-04, Vol.91 (4), p.1246-1253
• Main Authors: Camacho-Hübner, Cecilia, Rose, Stephen, Preece, Michael A., Sleevi, Mark, Storr, Helen L., Miraki-Moud, Farideh, Minuto, Francesco, Frystyk, Jan, Rogol, Alan, Allan, Geoffrey, Sommer, Andreas, Savage, Martin O.
• Format: Article
• Language: English
• Subjects: Adolescent; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Western; Body Mass Index; Carrier Proteins - metabolism; Dose-Response Relationship, Drug; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Glycoproteins - metabolism; Human Growth Hormone - physiology; Humans; Insulin-Like Growth Factor Binding Protein 3 - administration & dosage; Insulin-Like Growth Factor Binding Protein 3 - adverse effects; Insulin-Like Growth Factor Binding Protein 3 - pharmacokinetics; Insulin-Like Growth Factor I - administration & dosage; Insulin-Like Growth Factor I - adverse effects; Insulin-Like Growth Factor I - pharmacokinetics; Insulin-Like Growth Factor II - metabolism; Laron Syndrome - metabolism; Male; Medical sciences; Models, Statistical; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2005-1017

Context: 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 μg/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. Objectives: 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. Design: This was an open-label clinical study. Setting: The study was conducted in a general pediatric ward of a university teaching hospital. Participants: 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. Intervention: 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 μg/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. Conclusion: 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.