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

Abstract

Background: In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP.

Methods: In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900-1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47-168) h in dosages between 21 and 111 µg/kg/24 h.

Results: Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75-100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded.

Conclusion: In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe.

Trial registration: ClinicalTrials.gov NCT01096784.

Figures

Figure 1

Observed and model-predicted serum insulin-like growth factor-I (IGF-I) concentrations, in relation to postnatal age, in five very preterm children. The chronological age (days) is shown on the x-axis and serum IGF-I levels (µg/l) on the y-axis. (a) Patient 1; (b) patient 2; (c) patient 3; (d) patient 4; (e) patient 5. All the infants received continuous intravenous infusions of rhIGF-I/rhIGFBP-3. Population-predicted endogenous concentrations are shown for an untreated typical child with the same body weight as that of the treated subject. The individual predictions consider unexplained interindividual differences. The individual total predictions show the best model that fit the observed data and the administered doses of rhIGF-I/rhIGFBP-3. The observed values are depicted as circles, the individual-predicted endogenous serum IGF-I concentrations as a dotted line, the population- predicted endogenous serum IGF-I concentration as a broken line, and the individual-predicted total serum IGF-I as a solid line. rhIGF-I, recombinant human IGF-I; rhIGFBP, recombinant human IGF binding protein 3.

Figure 2

Predicted total and endogenous serum insulin-like growth factor-I (IGF-I) concentrations during continuous intravenous infusion of rhIGF-I/rhIGFBP-3 at doses of 75, 90, and 100 µg/kg/24 h, started at 12 h after birth, in an infant with a birth weight of 1,000 g. The endogenous IGF-I levels are depicted as a dotted line, the endogenous levels +75 µg/kg/24 h at 12 h are depicted as a dash-and-dot line, the endogenous levels +90 µg/kg/24 h at 12 h are depicted as a broken line, and the endogenous levels + 100 µg/kg/24 h at 12 h are depicted as a solid line. rhIGF-I, recombinant human IGF-I; rhIGFBP, recombinant human IGF binding protein 3.

Figure 3

Longitudinal serum insulin-like growth factor-I (IGF-I) (µg/l) (left y-axis), measured by radio-immunoassay, depicted as filled black circles connected with a solid black line, and plasma (p-) glucose (mmol/l) (right y-axis), depicted as filled gray squares connected with a dotted gray line, levels obtained during continuous infusion of rhIGF I/rhIGFBP-3 administered for 47–168 h in five very preterm infants. (a) Patient 1; (b) patient 2; (c) patient 3; (d) patient 4; and (e) patient 5. Chronological ages at infusion start and infusion stop of rhIGF-I/rhIGFBP-3 infusions are indicated by black arrows. Insulin treatment is indicated by a large open arrow. rhIGF-I, recombinant human IGF-I; rhIGFBP, recombinant human IGF binding protein 3.