A pharmacokinetic and dosing study of intravenous insulin-like growth factor-I and IGF-binding protein-3 complex to preterm infants

Abstract

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 microg/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.

Figures

Figure 1

A, Δ% IGF-I from baseline after 3h infusion of IGF-I/IGFBP-3 in different doses (n = 5) in five study subjects. Sampling time points are immediately before study drug infusion (−3), immediately following completed infusion of drug (0), and at 1, 2, 6, 12, 18, 24, and 48 h post completed drug infusion. One (880 g; 6 µg/kg); unfilled boxes and black line, 2 (1,220 g; 24 µg/kg); red filled circle and red line, 3 (760 g; 33 µg/kg); green filled triangles and green line, 4 (1,115 g; 33 µg/kg); dark blue rhomb and dark blue line, 5 (810 g; 59 µg/kg); light blue filled boxes and light blue line. B, Δ% IGFBP-3 from baseline after 3 h infusion of IGF-I/IGFBP-3 in different doses (n = 5) in five study subjects. Sampling time points are immediately before study drug infusion (−3), immediately following completed infusion of drug (0), and at 1, 2, 6, 12, 18, 24, and 48 h post completed drug infusion. 1 (880 g; 6 µg/kg); unfilled boxes and black line, 2 (1,220 g; 24 µg/kg); red filled circle and red line, 3 (760 g; 33 µg/kg); green filled triangles and green line 4 (1,115 g; 33 µg/kg); dark blue rhomb and dark blue line, 5 (810 g; 59 µg/kg); and light blue filled boxes and light blue line.

Figure 2

Heart rate (bpm) after 3 h infusion of IGF-I/IGFBP-3 in different doses (n = 5) in five study subjects. Sampling time points are immediately before study drug infusion (−3), immediately following completed infusion of drug (0) and thereafter at every hour up to 12 h post completed drug infusion. 1 (880 g; 6 µg/kg); unfilled boxes and black line, 2 (1,220 g; 24 µg/kg); red filled circle and red line, 3 (760 g; 33 µg/kg); green filled triangles and green line 4 (1,115 g; 33 µg/kg); dark blue rhomb and dark blue line, 5 (810 g; 59 µg/kg); and light blue filled boxes and light blue line.