Pilot dose-ranging of rhIGF-1/rhIGFBP-3 in a preterm lamb model of evolving bronchopulmonary dysplasia

BACKGROUND: Low levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine: (1) dosage of recombinant human (rh) IGF-1 bound to binding protein 3 (IGFBP3) to reach infant physiologic plasma levels; (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes. METHODS: Group 1: normal, unventilated lambs from 128d gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/Kg/d; n=2) for 3d in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/d dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in 4 more MV preterm lambs. RESULTS: Group 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 d gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/Kg/d rhIGF-1/rhIGFBP-3) in 6 MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes (p<0.1) compared to 6 MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs. CONCLUSIONS: Three days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/Kg/d improved some pulmonary and cardiovascular outcomes without toxicity.