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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

Department of Endocrinology, William Harvey Research Institute, Queen Mary, University of London (C.C.-H., H.L.S., F.M.-M., M.O.S.), London EC1M 6BQ, United Kingdom; Department of Pediatrics, Birmingham Heartland Hospital (S.R.), Birmingham B9 5SS, United Kingdom; Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health (M.A.P.), London WC1N 1EH, United Kingdom; Insmed, Inc. (M.S., A.R., G.A., A.S.), Glen Allen, Virginia 23060; Department of Endocrinology and Metabolism and Center of Excellence for Biomedical Research, University of Genoa (F.M.), Genoa I-16132, Italy; and Medical Research Laboratories and Medical Department, Nørrebrogade, Aarhus University Hospital (J.F.), Aarhus DK-8000, Denmark

Address all correspondence and requests for reprints to: Dr. Cecilia Camacho-Hübner, Department of Endocrinology, William Harvey Research Institute, John Vane Science Building, First Floor, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail: c.camacho-hubner{at}qmul.ac.uk.

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.

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