Assessment of compatibility of rhlGF-1/rhlGFBP-3 with neonatal intravenous medications

Background Recombinant human(rh)IGF-1/IGFBP-3 protein complex,administered as a continuous intravenous infusion in preterm infants,is being studied for the prevention of complications of prematurity.Methods We conducted in vitro studies to evaluate the physical and chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered to preterm neonates.In vitro mixing of rhIGF-1/IGFBP-3 drug product with small-molecule test medications plus corresponding controls was performed.Physical compatibility was defined as no color change,precipitation,turbidity,gas evolution,no clinically relevant change in pH/osmolality or loss in medication content.Chemical compatibility of small molecules was assessed using liquid chromatography(e.g.,reverse-phase HPLC and ion chromatography),with incompatibility defined as loss of concentration of≥10%.A risk evaluation was conducted for each medication based on in vitro compatibility data and potential for chemical modification.Results In vitro physical compatibility was established for 11/19 medications:caffeine citrate,fentanyl,fluconazole,gen-tamicin,insulin,intravenous fat emulsion,midazolam,morphine sulfate,custom-mixed parenteral nutrition solution(with/without electrolytes),parenteral nutrition solution+intravenous fat emulsion,and vancomycin(dosed from a 5 mg/mL solu-tion),but not for 8/19 medications:amikacin,ampicillin,dopamine,dobutamine,furosemide,meropenem,norepinephrine,and penicillin G,largely owing to changes in pH after mixing.Small-molecule compatibility was unaffected post-mixing,with no loss of small-molecule content.For physically compatible medications,risk analyses confirmed low probability and severity of a risk event.Conclusion Co-administration of rhIGF-1/rhIGFBP-3 drug product with various medications was assessed by in vitro studies using case-by-case risk analyses to determine the suitability of the products for co-administration.