Background Despite extensive co-administration of drugs to neonates, drug-drug compatibility has not gen-erally been tested before medicines are introduced to this population. Recombinant human (rh)IGF-1/IGFBP-3 (a protein complex) is being studied for the prevention of complications of prematurity, administered as a continuous intravenous (IV) infusion in preterm infants. Due to limited line access in neonates, coadministration with other medications via a terminal injection site would be desirable for use in clinical practice. A comprehensive risk assessment based on in vitro testing is evaluating the physical/chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered intravenously in the neonatal intensive care unit (NICU). We report initial re-sults from the panel of medications assessed to date.
Methods Medications most likely to be co-infused with rhIGF-1/IGFBP-3 were identified at the start of the risk as-sessment by consulting sites for a clinical trial. In vitro mix-ing of rhIGF-1/IGFBP-3 with each test medication (pre-dominantly small molecules) was performed based on different volumes and/or mass ratios to mimic different dose ranges. Duration of mixing was based on average infusion rates of rhIGF-1/IGFBP-3 with each test medica-tion at the highest dose, and an estimated volume for an umbilical catheter. Physical compatibility was assessed by visual observation, optical density at 320 nm, pH, and os-molality for each mixed solution and compared with the corresponding controls. Where there was no observed colour change, precipitation, turbidity, gas evolution or clinically relevant change in pH or osmolality, the mix-tures were considered compatible. The concentration of each test medication post-mixing was assessed using re-versed phase high performance liquid chromatography. A comprehensive risk evaluation was conducted for each medication based on the in vitro physical/chemical com-patibility data, theoretical potential for chemical modifi-cation, and clinical co-infusion history/experiences.
Results In vitro studies and risk evaluations have been completed for rhIGF-1/IGFBP-3 with 13 medications: do-pamine, parenteral nutrition (PN), PN+Intralipid 20%, Intr-alipid 20%, dobutamine, vancomycin, morphine, fentanyl, midazolam, fluconazole, caffeine citrate, amikacin and in-sulin. In vitro physical compatibility was established with 10/13 medications: parenteral nutrition (PN), PN+Intralip-id 20%, Intralipid 20%, dobutamine, vancomycin, mor-phine, fentanyl, midazolam, fluconazole and insulin. Phys-ical compatibility was not established with 3/13 medica-tions: dopamine, caffeine citrate and amikacin, owing to changes in pH post-mixing. Small molecule content was not affected post-mixing for the medications tested. A comprehensive risk evaluation confirmed a low risk for the probability/severity of a ‘risk event’ (defined as in-compatibility with the co-infused drug over the duration and condition of the simulated mixing studies) for those medications showing in vitro compatibility.
Conclusion Case-by-case, in vitro compatibility data for rhIGF-1/rhIGFBP-3 to date have been encouraging and indicate the likelihood of being able to co-infuse rhIGF-1/rhIGFBP-3 with the tested medicines. Further work is on-going to systematically evaluate compatibility with other IV drugs used in the NICU and develop protein-specific assays to test chemical compatibility of rhIGF-1/IGFBP-3. We believe this work will establish a new benchmark for compatibility testing of drugs utilised in neonates; con-tributions from clinicians and cross-functional disciplines will be key to the process.
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