Development of Protein-Specific Analytical Methodologies to Evaluate Compatibility of Recombinant Human (rh)IGF-1/rhIGFBP-3 with Intravenous Medications Co-Administered to Neonates

Salamat‐Miller, Nazila; Qu, Wanlu; Chadwick, Jennifer S.; McPherson, Christopher; Salinas, Paul A.; Turner, Mark A.; Wang, Dongdong; Barton, Norman W.

doi:10.1016/j.xphs.2021.10.027

Cited by 3 publications

(6 citation statements)

References 19 publications

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“… IGF-1 insulin-like growth factor-1, IGFBP-3 insulin-like growth factor binding protein-3, N/A not applicable, PN parenteral nutrition, rh recombinant human, RP-HPLC reversed-phase high-performance liquid chromatography a To date, on the basis of these studies and protein-specific analyses, this medication has been removed from the incompatible list of medications. The protein-specific analyses demonstrated that the observed pH and osmolality changes did not cause fragmentation, oxidation, aggregation, adduct formation, and generation of any free rhIGF-1 or rhlGFBP-3 submolecular units b “Development of Protein-Specific Analytical Methodologies to Evaluate Compatibility of Recombinant Human (rh)IGF-1/rhIGFBP-3 with Intravenous Medications Co-Administered to Neonates” c Compatible based on the physical data; however, the final compatibility decision is informed by other studies [ 18 ] …”

Section: Resultsmentioning

confidence: 99%

“…c Compatible based on the physical data; however, the final compatibility decision is informed by other studies [ 18 ]…”

Section: Resultsmentioning

confidence: 99%

“…The protein-specific analyses demonstrated that the observed pH and osmolality changes did not cause fragmentation, oxidation, aggregation, adduct formation, and generation of any free rhIGF-1 or rhlGFBP-3 submolecular units b "Development of Protein-Specific Analytical Methodologies to Evaluate Compatibility of Recombinant Human (rh)IGF-1/rhIGFBP-3 with Intravenous Medications Co-Administered to Neonates" c Compatible based on the physical data; however, the final compatibility decision is informed by other studies [18] In this study we investigated the physical compatibility of the rhIGF-1/rhIGFBP-3 drug product when mixed with frequently administered medications. To generate a complete picture of compatibility, we evaluated chemical compatibility at the level of the small-molecule content as part of a separate study on the protein content/chemical modification [18]. It should be noted that the main challenge with the protein-specific methodologies is the extremely low protein concentration of rhIGF-1/rhIGFBP-3 post mixing with each small molecule.…”

Section: Discussionmentioning

confidence: 99%

“…Sensitive mass spectrometry-based protein-specific methodologies have been developed by Takeda to assess the chemical compatibility of the rhIGF-1/rhIGFBP-3 drug product. The development of protein-specific methodologies is reported separately [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

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Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications

et al. 2022

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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, gentamicin, 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 solution), 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.

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Section: Resultsmentioning

confidence: 99%

“…c Compatible based on the physical data; however, the final compatibility decision is informed by other studies [ 18 ]…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications

et al. 2022

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“…However, this drug was removed from the market in 2007 due to patent infringement. Studies of mecasermin rinfabate as a continuous infusion to prevent bronchopulmonary dysplasia in premature infants are ongoing [115].…”

Section: Igf Therapy: Success But Also Limitationsmentioning

confidence: 99%

The History of the Insulin-Like Growth Factor System

2022

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The growth hormone (GH)–insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

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A cleavable self-aggregating tag scheme for the expression and purification of disulfide bonded proteins and peptides

Lin

Jing

Huang

et al. 2022

Chemical Engineering Science

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Development of Protein-Specific Analytical Methodologies to Evaluate Compatibility of Recombinant Human (rh)IGF-1/rhIGFBP-3 with Intravenous Medications Co-Administered to Neonates

Cited by 3 publications

References 19 publications

Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications

Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications

The History of the Insulin-Like Growth Factor System

A cleavable self-aggregating tag scheme for the expression and purification of disulfide bonded proteins and peptides

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