Salamat-Miller, Nazila, Qu, Wanlu, Chadwick, Jennifer S, McPherson, Christopher, Salinas, Paul A, Turner, Mark 
ORCID: 0000-0002-5299-8656, Wang, Dongdong and Barton, Norman
(2021)
Development of Protein-Specific Analytical Methodologies to Evaluate Compatibility of Recombinant Human (rh)IGF-1/rhIGFBP-3 with Intravenous Medications Co-Administered to Neonates.
Journal of Pharmaceutical Sciences, 111 (5).
pp. 1486-1496.
Abstract
The protein complex of recombinant human insulin-like growth factor-1 and insulin‑like growth factor binding protein‑3 (rhIGF-1/rhIGFBP-3; mecasermin rinfabate), is an investigational product for the prevention of complications of prematurity. Delivery of rhIGF-1/rhIGFBP-3 is by continuous central line intravenous infusion in preterm infants until endogenous IGF-1 production begins. Protein-specific analytical methodologies were developed to evaluate the compatibility of rhIGF-1/rhIGFBP-3 at low protein concentrations (∼2.5-10 μg/mL) expected when co-administered with other required medications in the NICU. Highly sensitive detection of the biologic potential degradants (fragments) and/or molecular modifications (oxidized species, aggregates) required the use of reversed-phase high-performance liquid chromatography and size-exclusion ultra-performance liquid chromatography coupled with mass spectrometric detection. We report on the quantification of rhIGF-1/rhIGFBP-3, its components and degradants, to a limit of quantitation of 3.1 μg/mL upon mixing with 24 commonly administered neonatal medications. Methods developed for the rhIGF-1/rhIGFBP-3 admixtures, optimized in studies with furosemide, caffeine citrate and ampicillin, demonstrated good reproducibility, linearity, and limit of detection/quantitation. Using these methods, no increase in degradation of rhIGF-1/rhIGFBP-3 components and no increase in oxidation or aggregation level was observed with caffeine citrate, while admixtures of rhIGF-1/rhIGFBP-3 with ampicillin yielded lower mass recovery of rhIGF-1/rhIGFBP-3 components, which likely resulted from adduct formation. Furosemide was found to be physically incompatible with rhIGF-1/rhIGFBP-3. Our findings support the use of these methodologies for detection of protein modifications under various clinical administration conditions, and additionally supplement physical compatibility data studies of ultra-low concentrations of rhIGF-1/rhIGFBP-3 post co-administration to preterm infants with other medications (manuscript in-preparation).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Biopharmaceutical characterization, Physical stability, Protein aggregation, Degradation product(s), HPLC (high-performance, pressure liquid, chromatography), Liquid Chromatography-Mass spectrometry, (LC-MS) |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 08 Dec 2021 10:53 |
| Last Modified: | 18 Jan 2023 21:23 |
| DOI: | 10.1016/j.xphs.2021.10.027 |
| Open Access URL: | https://doi.org/10.1016/j.xphs.2021.10.027 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3144941 |
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