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Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.
Br J Haematol. 2020 May 24 [Online ahead of print]BJ

Abstract

Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.

Authors+Show Affiliations

French Reference Center for Aplastic Anemia and PNH Hematology-Bone Marrow Transplantation, Hôpital Saint-Louis AP-HP, Paris, France. Université Paris Diderot, Paris, France.Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.Alexion Pharmaceuticals, Inc., Boston, MA, USA.Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea.Department of Haematology, St. James's University Hospital, Leeds, UK.Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia.Department of Haematological Medicine, King's College Hospital, NIHR/Wellcome King's Clinical Research Facility, London, UK.Alexion Pharmaceuticals, Inc., Boston, MA, USA.Alexion Pharmaceuticals, Inc., Boston, MA, USA.Alexion Pharmaceuticals, Inc., Boston, MA, USA.Division of Medical Oncology and Haematology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.Clinical Haematology at Peter MacCallum Cancer Centre, The Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32449174

Citation

Peffault de Latour, Régis, et al. "Pharmacokinetic and Pharmacodynamic Effects of Ravulizumab and Eculizumab On Complement Component 5 in Adults With Paroxysmal Nocturnal Haemoglobinuria: Results of Two Phase 3 Randomised, Multicentre Studies." British Journal of Haematology, 2020.
Peffault de Latour R, Brodsky RA, Ortiz S, et al. Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies. Br J Haematol. 2020.
Peffault de Latour, R., Brodsky, R. A., Ortiz, S., Risitano, A. M., Jang, J. H., Hillmen, P., Kulagin, A. D., Kulasekararaj, A. G., Rottinghaus, S. T., Aguzzi, R., Gao, X., Wells, R. A., & Szer, J. (2020). Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies. British Journal of Haematology. https://doi.org/10.1111/bjh.16711
Peffault de Latour R, et al. Pharmacokinetic and Pharmacodynamic Effects of Ravulizumab and Eculizumab On Complement Component 5 in Adults With Paroxysmal Nocturnal Haemoglobinuria: Results of Two Phase 3 Randomised, Multicentre Studies. Br J Haematol. 2020 May 24; PubMed PMID: 32449174.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies. AU - Peffault de Latour,Régis, AU - Brodsky,Robert A, AU - Ortiz,Stephan, AU - Risitano,Antonio M, AU - Jang,Jun H, AU - Hillmen,Peter, AU - Kulagin,Alexander D, AU - Kulasekararaj,Austin G, AU - Rottinghaus,Scott T, AU - Aguzzi,Rasha, AU - Gao,Xiang, AU - Wells,Richard A, AU - Szer,Jeff, Y1 - 2020/05/24/ PY - 2019/11/06/received PY - 2020/04/10/accepted PY - 2020/5/26/entrez KW - L-lactate dehydrogenase KW - complement C5 KW - eculizumab KW - half-life KW - ravulizumab JF - British journal of haematology JO - Br. J. Haematol. N2 - Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH. SN - 1365-2141 UR - https://www.unboundmedicine.com/medline/citation/32449174/Pharmacokinetic_and_pharmacodynamic_effects_of_ravulizumab_and_eculizumab_on_complement_component_5_in_adults_with_paroxysmal_nocturnal_haemoglobinuria:_results_of_two_phase_3_randomised_multicentre_studies_ L2 - https://doi.org/10.1111/bjh.16711 DB - PRIME DP - Unbound Medicine ER -