Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety (original) (raw)
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Pediatric Research, 2009
In preterm infants, low levels of Insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 g/kg. The study was conducted at Queen Silvia Children's Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26 -29) and birth weight 1022 g (810 -1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12-28) and 771 (651-1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25-59) and 838 (754 -1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59 -1.42) and 0.87 (0.85-0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated. (Pediatr Res 65: 574-579, 2009) Abbreviations: ALS, acid-labile subunit; CL, clearence; FFP, fresh frozen plasma; GHIS, growth hormone insensitivity syndrome; IGFBP-3, insulin like growth factor binding protein 3 0031-3998/09/6505-0574 PEDIATRIC RESEARCH
IGF-1 as a drug for preterm infants: a step-wise clinical development
Current pharmaceutical design, 2017
Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation. After very preterm birth, energy demands increase while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral nutrition for weeks. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain, retinopathy of prematurity (ROP) and other morbidities. We will describe the process by which we aim to develop supplementation with recombinant human (rh) IGF-1 and its binding protein rhIGFBP-3 as a possible therapy to promote growth and maturation and reduce morbidities in extremely preterm infants. In order to calculate a dose of IGF-1 tolerated by neonates, a pharmacokinetic study of transfusion with fresh frozen plasma was performed, which provided a relatively low dose of IGF-1, (on average 1.4 μg/kg), that increased serum IGF-1 to levels close to those obse...
Regulatory Peptides, 1993
Cord sera were obtained from 44 term, human infants exhibiting various patterns of intrauterine growth and were assayed for IGF-1, IGF-2, and IGFBP-1, 2, and 3 by specific RIAs. Serum levels were correlated with birth weight (BW), ponderal index (PI), and placental weight (PW). Total IGF-1 levels correlated significantly with BW (r = 0.392), PW (r = 0.351), and PI (r = 0.481). By contrast, the correlation of IGF-2 with birth weight was not statistically significant (r= 0.264, P= 0.091). The association of IGF-2 with PI, however, was significant (r = 3.348, P = 0.024). IGFBP-3 exhibited significant correlations with BW, PI, and PW, similar to those seen with IGF-1. IGFBP-1 and IGFBP-2, however, were not significantly related to growth parameters. IGF-1 levels correlated strongly with IGFBP-3 levels (r= 0.646, P= 0.001). By contrast, IGF-1 correlated with the reciprocal of both IGFBP-1 and IGFBP-2. Based upon in vitro affinity constants, theoretical concentrations for each [IGF/IGFBP] complex, free IGFs, and free IGFBPs were calculated for each infant. Multiple regression analysis was performed including all 11 calculated variables and correlated with each growth parameter. This analysis revealed that an integrated expression of IGF activity exhibited stronger correlations with growth than each individual peptide species (BW, r = 0.681; PI, r = 0.660; PW, r = 0.658). These data further support roles for IGF related peptides (IGFRPs) in human fetal and placental growth and suggest regulatory/ counterregulatory roles for the IGFBPs. It also supports the hypothesis that individual IGFRPs interact in a complex manner to define 'net IGF activity' in relation to fetal growth and/or metabolic status.
Early Human Development, 1996
Cord sera were obtained from term, Chilean newborns exhibiting various patterns of intrauterine growth and assayed for IGF-I, IGF-2, IGFBP-I, IGPBP-2, and IGFESP-3 by specific radioimmunoassays @IA). Serum levels of each peptide were correlated with birth weight (BW), ponderal index (PI), and placental weight (PW). Total IGF-I levels correlated with BW (r = 0.665, P = O.OOOl), PI (r = 0.527, P = 0.004), and PW (r = 0.596, P = 0.0017). Iu contrast, IGF-2 failed to correlate with any growth parameter. Of the three binding proteins, IGFEP-3 exhibited the strongest relationship to each growth parameter. IGPIW-3 correlated significantly with BW (r = 0.71, P i O.OOOl), PI (r = 0.782, P < O.OOOl), and PW (r = 0.57, P = 0.0029). In addition IGFFSP-3 levels positively correlated to IGF-1 levels (r = 0.614, P = 0.0005). By contrast, circulating IGFBP-1 and IGFBP-2 were inversely related to IGF-I levels. A11 five peptides were subjected to multiple regression analysis and *Corresponding author. Tel.: + 1 314 4542114; fax: + 1 314 7217480 0378-3782/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PIf SO378-3782(96)01737-9 16 M. Osorio et al. I Early Hutnan Development 46 (1996) 15-26
Fetal Therapy with rhIGF-1 in a Rabbit Model of Intrauterine Growth Retardation
Journal of Surgical Research, 2001
Background. Intrauterine growth retardation (IUGR) may, in part, be due to a deficiency of insulinlike growth factor-1 (IGF-1). The objectives of this study were to determine the relationship between fetal serum IGF-1 levels and fetal and placental size in a rabbit model of IUGR and to compare two techniques of selective, exogenous IGF-1 administration (transamniotic and branch uterine arterial catheter infusion) to growth-retarded fetuses in utero.
The Journal of Clinical Endocrinology & Metabolism, 2000
Experimental rodent studies demonstrate that insulin-like growth factor II (IGF-II) promotes fetal growth, whereas the nonsignaling IGF-II receptor (IGF2R) is inhibitory; in humans their influence is as yet unclear. A soluble, circulating form of IGF2R inhibits IGF-II mediated DNA synthesis and may therefore restrain fetal growth. We measured cord blood levels of IGF-II, soluble IGF2R, insulin, IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and examined their relationships to weight, length, head circumference, ponderal index, and placental weight at birth in 199 normal term singletons. IGF-II levels correlated with levels of IGF-I (r ϭ 0.29; P Ͻ 0.0005), IGFBP-3 (r ϭ 0.45; P Ͻ 0.0005), and soluble IGF2R (r ϭ 0.20; P Ͻ 0.005). Insulin
rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial
The Journal of Pediatrics
and on behalf of the study team* Objective To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. Study design This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 23 0/7 weeks to 27 6/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 29 6/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 40 4/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. Results Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. Conclusions rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage.