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

Camacho‐Hübner, Cecilia; Rose, Stephen; Preece, M A; Sleevi, M.; Storr, Helen L; Miraki-Moud, Farideh; Minuto, Francesco; Frystyk, Jan; Rogol, Alan D.; Allan, Geoffrey; Sommer, Andreas; Savage, Martin O.

doi:10.1210/jc.2005-1017

Cited by 43 publications

(33 citation statements)

References 30 publications

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“…Less clear, however, is the specific effect(s) of the STAT5b mutations on immune function(s), although recurring pulmonary infections appear to be a common consequence. Finally, while GH therapy to correct the poor linear growth would be predicted to be ineffective for these patients, it is possible that treatment with IGF-I or IGF-I/IGFBP-3 complex would be of clinical value, as has been demonstrated for patients with other forms of primary IGF deficiency [19,20,21,22,23], and is currently under consideration for the present subjects.…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone Insensitivity and Severe Short Stature in Siblings: A Novel Mutation at the Exon 13-Intron 13 Junction of the <i>STAT5b</i> Gene

et al. 2007

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Background/Aims: Growth hormone insensitivity (GHI) is characterized by severe short stature, high serum growth hormone (GH), low serum IGF-I and IGFBP-3 levels and is classically associated with genetic defects of the GH receptor (GHR). Recently, mutations of the STAT5b gene have been identified and shown to be associated with GHI and severe IGF deficiency. We investigated 2 sisters from a consanguineous family from Kuwait, with clinical and biochemical features of GHI, in whom no molecular defects in the GHR were identified. Methods: Serum and DNA were analyzed. Results: In addition to GHI, siblings 2 and 1 presented with, respectively, a diagnosis of juvenile idiopathic arthritis and recurrent pulmonary infections. Molecular analysis of the STAT5b gene revealed a novel homozygous deletion of a G at the junction of exon 13-intron 13. The parents, who are of normal height, were heterozygous for the mutation. Conclusions: This is the first STAT5b defect to be identified in siblings, further supporting the autosomal recessive mode of transmission of STAT5b deficiency. The results affirm that defective STAT5b is an etiology for IGF deficiency and the GHI phenotype, and emphasize the importance of considering this diagnosis in patients with IGF deficiency, especially when associated with diverse immunological problems.

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Section: Discussionmentioning

confidence: 99%

Growth Hormone Insensitivity and Severe Short Stature in Siblings: A Novel Mutation at the Exon 13-Intron 13 Junction of the <i>STAT5b</i> Gene

et al. 2007

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“…Moreover, pharmacological studies of an IGF-I compound containing a 1:1 molar complex of rhIGF-I and rhIGFBP-3 (IGF-binding protein; Insmed, Inc., Glen Allen, Va., USA) demonstrated that the complex was effective in increasing levels of circulating total and free IGF-I and that the administration in patients with GHIS should be safe and well-tolerated [4]. In addition, it was even hypothesized that this complex mimics the physiological effects of IGF-I with a more favorable pharmacokinetic profile [4]. …”

Section: Introductionmentioning

confidence: 99%

Insulin-Like Growth Factor-I Treatment in Primary Growth Hormone Insensitivity: Effect of Recombinant Human IGF-I (rhIGF-I) and rhIGF-I/rhIGF-Binding Protein-3 Complex

Tonella

Flück²,

Mullis³

2010

Horm Res Paediatr

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Background/Aims: Growth hormone insensitivity syndrome (GHIS) is a rare cause of growth retardation characterized by high serum GH levels, and low serum insulin-like growth factor I (IGF-I) levels associated with a genetic defect of the GH receptor (GHR) as well post-GHR signaling pathway. Based on clinical, as well as biochemical characteristics, GHIS can be genetically classified as classical/Laron’s syndrome and nonclassical/atypical GHIS. Recombinant human IGF-I (rhIGF-I) treatment is effective in promoting growth in subjects who have GHIS. Further, pharmacological studies of a IGF-I compound containing a 1:1 molar complex of rhIGF-I and rhIGF-binding protein-3 (BP-3) demonstrated that the complex was effective in increasing levels of circulating total and free IGF-I and that the administration in patients with GHIS should be safe, well-tolerated and more effective than rhIGF-I on its own. Patient/Methods: We describe the long-term effect of various IGF-I preparations (rhIGF; rhIGF-I/rhIGFBP-3) in a single subject treated for more than 14 years while focusing on height, height velocity as well as on additional auxological and laboratory data. Results: This study confirms that rhIGF-I is effective in promoting growth in children with GHIS. However, on the combined rhIGF-I/rhIGFBP-3 treatment as well as off rhIGF-I therapy the height velocity decreased drastically (2 and 1.8 cm vs. overall 6.5 cm/year on rhIGF-I, respectively). On rhIGF-I treatment, serum IGF-I was found to be well within the normal range, whereas serum IGFBP-3 remained low. On the rhIGF-I/rhIGFBP-3 compound therapy, however, serum IGFBP-3 increased into the normal range, which was not the case for serum IGF-I. Importantly, the increase of the serum IGFBP-3 level excludes noncompliance. In addition, body mass index as well as dual-energy X-ray absorptiometry analysis underlined the positive effect of rhIGF-I treatment on body composition. Conclusions:The rhIGF-I/rhIGFBP-3 compound therapy seems to be not efficient in treating this individual patient with GHIS when compared with rhIGF-I alone.

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“…37 Preliminary uncontrolled studies, on treatment of IGFD with the complexes of IGF1/IGFBP-3 (mecasermin rinfabate), showed extension of serum IGF-1 half life and normalization of serum levels of IGF1, but failed to demonstrate an improvement in growth rate, compared to treatment with rhIGF1 alone. 17,34 Unpublished data 35 demonstrated that patients receiving rhIGF1/IGFBP-3 at a dose equivalent to a daily dose of rhIGF1 of 200 µg/kg showed an increase in height velocity only of 3 cm/year. Patients treated with higher dose of the complex comparable to 400 µg/kg of rhIGF1 per day showed an increment in growth rate of 6.3 cm/year.…”

Section: Dovepressmentioning

confidence: 99%

“…The 24 hour area under the curve (AUC) was comparable between rhIGF1 therapy and the higher combination dose, while it was less for the lower combination dose. 34 The comparable levels of circulating IGF-1 either in patients treated with rhIGF1 alone or with the complex, may be explained by the possible binding of IGF-1 to other IGFBPs. Indeed, IGFBP-2 is elevated in IGFD patients and increases with rhIGF1 therapy.…”

Section: Dovepressmentioning

confidence: 99%

Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency

Fintini¹,

Baratto²,

Cappa³

2009

TCRM

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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

Cited by 43 publications

References 30 publications

Growth Hormone Insensitivity and Severe Short Stature in Siblings: A Novel Mutation at the Exon 13-Intron 13 Junction of the <i>STAT5b</i> Gene

Growth Hormone Insensitivity and Severe Short Stature in Siblings: A Novel Mutation at the Exon 13-Intron 13 Junction of the <i>STAT5b</i> Gene

Insulin-Like Growth Factor-I Treatment in Primary Growth Hormone Insensitivity: Effect of Recombinant Human IGF-I (rhIGF-I) and rhIGF-I/rhIGF-Binding Protein-3 Complex

Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency

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