Cargando…

Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin‐6 (IL‐6), soluble IL‐6 receptor, and C‐reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02...

Descripción completa

Detalles Bibliográficos
Autores principales: Paccaly, Anne J., Kovalenko, Pavel, Parrino, Janie, Boyapati, Anita, Xu, Christine, van Hoogstraten, Hubert, Ishii, Tomonori, Davis, John D., DiCioccio, A. Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754484/
https://www.ncbi.nlm.nih.gov/pubmed/32726514
http://dx.doi.org/10.1002/jcph.1703
_version_ 1783626206125490176
author Paccaly, Anne J.
Kovalenko, Pavel
Parrino, Janie
Boyapati, Anita
Xu, Christine
van Hoogstraten, Hubert
Ishii, Tomonori
Davis, John D.
DiCioccio, A. Thomas
author_facet Paccaly, Anne J.
Kovalenko, Pavel
Parrino, Janie
Boyapati, Anita
Xu, Christine
van Hoogstraten, Hubert
Ishii, Tomonori
Davis, John D.
DiCioccio, A. Thomas
author_sort Paccaly, Anne J.
collection PubMed
description We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin‐6 (IL‐6), soluble IL‐6 receptor, and C‐reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single‐dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target‐mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7‐15 days for CRP and 3‐5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.
format Online
Article
Text
id pubmed-7754484
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-77544842020-12-28 Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate Paccaly, Anne J. Kovalenko, Pavel Parrino, Janie Boyapati, Anita Xu, Christine van Hoogstraten, Hubert Ishii, Tomonori Davis, John D. DiCioccio, A. Thomas J Clin Pharmacol Pharmacokinetics/Pharmacodynamics We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin‐6 (IL‐6), soluble IL‐6 receptor, and C‐reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single‐dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target‐mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7‐15 days for CRP and 3‐5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies. John Wiley and Sons Inc. 2020-07-29 2021-01 /pmc/articles/PMC7754484/ /pubmed/32726514 http://dx.doi.org/10.1002/jcph.1703 Text en © 2020 Regeneron Pharmaceuticals, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Pharmacokinetics/Pharmacodynamics
Paccaly, Anne J.
Kovalenko, Pavel
Parrino, Janie
Boyapati, Anita
Xu, Christine
van Hoogstraten, Hubert
Ishii, Tomonori
Davis, John D.
DiCioccio, A. Thomas
Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate
title Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate
title_full Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate
title_fullStr Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate
title_full_unstemmed Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate
title_short Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate
title_sort pharmacokinetics and pharmacodynamics of subcutaneous sarilumab and intravenous tocilizumab following single‐dose administration in patients with active rheumatoid arthritis on stable methotrexate
topic Pharmacokinetics/Pharmacodynamics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754484/
https://www.ncbi.nlm.nih.gov/pubmed/32726514
http://dx.doi.org/10.1002/jcph.1703
work_keys_str_mv AT paccalyannej pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT kovalenkopavel pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT parrinojanie pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT boyapatianita pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT xuchristine pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT vanhoogstratenhubert pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT ishiitomonori pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT davisjohnd pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate
AT dicioccioathomas pharmacokineticsandpharmacodynamicsofsubcutaneoussarilumabandintravenoustocilizumabfollowingsingledoseadministrationinpatientswithactiverheumatoidarthritisonstablemethotrexate