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A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects
This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two‐part phase I study (an...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9199881/ https://www.ncbi.nlm.nih.gov/pubmed/35301810 http://dx.doi.org/10.1111/cts.13271 |
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author | Ucpinar, Sibel Darpo, Borje Neale, Ann Nunn, Philip Shu, Jin Chu, Katherine A. Kavanagh, Marianne Xue, Hongqi Phiasivongsa, Pasit Thomas, Dolca Smith, Patrick F. |
author_facet | Ucpinar, Sibel Darpo, Borje Neale, Ann Nunn, Philip Shu, Jin Chu, Katherine A. Kavanagh, Marianne Xue, Hongqi Phiasivongsa, Pasit Thomas, Dolca Smith, Patrick F. |
author_sort | Ucpinar, Sibel |
collection | PubMed |
description | This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two‐part phase I study (anzctr.org.au ACTRN12618001036202). Part A was a randomized, open‐label, three‐period, single‐dose crossover study (n = 12) with rilzabrutinib 100 mg ± ritonavir 100 mg or rilzabrutinib 1200 mg. Part B was a randomized, double‐blind, placebo‐controlled, four‐way, single‐dose crossover study (n = 39) with matched placebo, rilzabrutinib 400 mg ± ritonavir 100 mg, or moxifloxacin (positive control). Primary objectives: part A – pharmacokinetics (PK) of rilzabrutinib ± ritonavir, safety, and optimal dose for Part B; Part B – effect of rilzabrutinib therapeutic and supratherapeutic concentration on electrocardiogram (ECG) parameters. ECGs and PK samples were serially recorded before and post‐dose. In part A, rilzabrutinib 100 mg + ritonavir led to 17‐fold area under the concentration–time curve (AUC(0–∞)) and 7‐fold maximum plasma concentration (C(max)) increases over rilzabrutinib alone. Rilzabrutinib 1200 mg was discontinued due to mild‐to‐moderate gastrointestinal intolerance. In Part B, rilzabrutinib 400 mg + ritonavir increased rilzabrutinib mean AUC(0–∞) from 454 to 3800 ng h/mL and C(max) from 144 to 712 ng/mL. The concentration–QTc relationship was slightly negative, shallow (−0.01 ms/ng/mL [90% CI −0.016 to −0.001]), and an effect >10 ms on QTcF could be excluded within the observed range of plasma concentrations, up to 2500 ng/mL. Safety was similar to other studies of rilzabrutinib. In conclusion, rilzabrutinib, even at supratherapeutic doses, had no clinically relevant effects on ECG parameters, including the QTc interval. |
format | Online Article Text |
id | pubmed-9199881 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91998812022-06-23 A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects Ucpinar, Sibel Darpo, Borje Neale, Ann Nunn, Philip Shu, Jin Chu, Katherine A. Kavanagh, Marianne Xue, Hongqi Phiasivongsa, Pasit Thomas, Dolca Smith, Patrick F. Clin Transl Sci Research This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two‐part phase I study (anzctr.org.au ACTRN12618001036202). Part A was a randomized, open‐label, three‐period, single‐dose crossover study (n = 12) with rilzabrutinib 100 mg ± ritonavir 100 mg or rilzabrutinib 1200 mg. Part B was a randomized, double‐blind, placebo‐controlled, four‐way, single‐dose crossover study (n = 39) with matched placebo, rilzabrutinib 400 mg ± ritonavir 100 mg, or moxifloxacin (positive control). Primary objectives: part A – pharmacokinetics (PK) of rilzabrutinib ± ritonavir, safety, and optimal dose for Part B; Part B – effect of rilzabrutinib therapeutic and supratherapeutic concentration on electrocardiogram (ECG) parameters. ECGs and PK samples were serially recorded before and post‐dose. In part A, rilzabrutinib 100 mg + ritonavir led to 17‐fold area under the concentration–time curve (AUC(0–∞)) and 7‐fold maximum plasma concentration (C(max)) increases over rilzabrutinib alone. Rilzabrutinib 1200 mg was discontinued due to mild‐to‐moderate gastrointestinal intolerance. In Part B, rilzabrutinib 400 mg + ritonavir increased rilzabrutinib mean AUC(0–∞) from 454 to 3800 ng h/mL and C(max) from 144 to 712 ng/mL. The concentration–QTc relationship was slightly negative, shallow (−0.01 ms/ng/mL [90% CI −0.016 to −0.001]), and an effect >10 ms on QTcF could be excluded within the observed range of plasma concentrations, up to 2500 ng/mL. Safety was similar to other studies of rilzabrutinib. In conclusion, rilzabrutinib, even at supratherapeutic doses, had no clinically relevant effects on ECG parameters, including the QTc interval. John Wiley and Sons Inc. 2022-04-03 2022-06 /pmc/articles/PMC9199881/ /pubmed/35301810 http://dx.doi.org/10.1111/cts.13271 Text en © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://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 | Research Ucpinar, Sibel Darpo, Borje Neale, Ann Nunn, Philip Shu, Jin Chu, Katherine A. Kavanagh, Marianne Xue, Hongqi Phiasivongsa, Pasit Thomas, Dolca Smith, Patrick F. A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects |
title | A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects |
title_full | A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects |
title_fullStr | A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects |
title_full_unstemmed | A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects |
title_short | A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects |
title_sort | thorough qtc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9199881/ https://www.ncbi.nlm.nih.gov/pubmed/35301810 http://dx.doi.org/10.1111/cts.13271 |
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