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Tytuł pozycji:

Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019.

Tytuł :
Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019.
Autorzy :
McEneny-King AC; Clinical Development and Translational Sciences, Clinical Pharmacology, Alexion Pharmaceuticals, Boston, MA, USA.
Monteleone JPR; Clinical Development and Translational Sciences, Pharmacometrics, Alexion Pharmaceuticals, Boston, MA, USA.
Kazani SD; Clinical Development and Translational Sciences, Alexion Pharmaceuticals, Boston, MA, USA.
Ortiz SR; Clinical Development and Translational Sciences, Clinical Pharmacology, Alexion Pharmaceuticals, Boston, MA, USA. .
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Źródło :
Infectious diseases and therapy [Infect Dis Ther] 2021 Jun; Vol. 10 (2), pp. 1045-1054. Date of Electronic Publication: 2021 Apr 07.
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Publication: 2014- : [Auckland] Adis
Original Publication: [London] : Springer Healthcare
References :
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Java A, Apicelli AJ, Liszewski MK, et al. The complement system in COVID-19: friend and foe? JCI Insight. 2020;5(15):e140711. (PMID: 10.1172/jci.insight.140711)
Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27(6):992 e3-1000 e3. (PMID: 10.1016/j.chom.2020.04.009)
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Tiwari R, Mishra AR, Mikaeloff F, et al. In silico and in vitro studies reveal complement system drives coagulation cascade in SARS-CoV-2 pathogenesis. Comput Struct Biotechnol J. 2020;18:3734–44. (PMID: 10.1016/j.csbj.2020.11.005)
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Carvelli J, Demaria O, Vely F, et al. Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature. 2020;588(7836):146–50. (PMID: 10.1038/s41586-020-2600-6)
Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1–13. (PMID: 10.1016/j.trsl.2020.04.007)
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D’Alessandro A, Thomas T, Dzieciatkowska M, et al. Serum proteomics in COVID-19 patients: altered coagulation and complement status as a function of IL-6 level. J Proteome Res. 2020;19(11):4417–27. (PMID: 10.1021/acs.jproteome.0c00365)
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Contributed Indexing :
Keywords: Antibodies; Complement C5/antagonists and inhibitors; Complement inactivating agents/therapeutic use; Coronavirus disease 2019; Humanized/therapeutic use; Monoclonal; Ravulizumab; Terminal complement pathway
Local Abstract: [plain-language-summary] While many people have no or mild COVID-19 symptoms, a small number of people become very sick and require hospitalization in intensive care units. One part of their immune system, known as complement, overreacts and attacks the lungs and other organs. Researchers are looking for a way to keep the immune system from attacking the body instead of protecting it. Ravulizumab is a medication currently used to do this in other diseases. Ravulizumab is being studied to see if it can reduce the destructive and deadly effects of the coronavirus infection. In this evaluation, ravulizumab effectively reduced complement in patients with severe COVID-19.
Molecular Sequence :
ClinicalTrials.gov NCT04369469
Entry Date(s) :
Date Created: 20210407 Latest Revision: 20210513
Update Code :
20211105
PubMed Central ID :
PMC8024938
DOI :
10.1007/s40121-021-00425-7
PMID :
33826106
Czasopismo naukowe
Introduction: Terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted. This analysis evaluates preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen.
Methods: Weight-based ravulizumab doses were administered on days 1, 5, 10, and 15. Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22. Free C5 levels < 0.5 μg/mL indicate complete C5 inhibition. The pharmacokinetic target was defined as ravulizumab concentrations at the end of the dosing interval > 175 μg/mL, the concentration above which C5 is completely inhibited.
Results: Twenty-two patients were included in this evaluation. At baseline, mean C5 concentration was 240 ± 67 μg/mL. In all patients and at all individual timepoints after the first dose was administered, ravulizumab concentrations remained > 175 μg/mL and free C5 concentrations remained < 0.5 μg/mL.
Conclusion: High levels of baseline C5 observed in patients with severe COVID-19 contribute to the growing body of evidence that suggests this disease is marked by amplification of terminal complement activation. Data from this preliminary pharmacokinetic/pharmacodynamic evaluation of 22 patients with severe COVID-19 show that the modified ravulizumab dosing regimen achieved immediate and complete terminal complement inhibition, which can be sustained for up to 22 days. These data support the continued use of this dosage regimen in the ongoing phase 3 study.
Trial Registration: ClinicalTrials.gov identifier, NCT04369469.

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