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Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor

This phase I study (CO‐338‐044; NCT02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly(ADP‐ribose) polymerase (PARP) inhibitor rucaparib on the pharmacokinetics (PK) of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 (C...

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Autores principales: Xiao, Jim J., Nowak, Dorota, Ramlau, Rodryg, Tomaszewska‐Kiecana, Monika, Wysocki, Piotr J., Isaacson, Jeff, Beltman, Jeri, Nash, Eileen, Kaczanowski, Robert, Arold, Gerhard, Watkins, Simon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342242/
https://www.ncbi.nlm.nih.gov/pubmed/30427584
http://dx.doi.org/10.1111/cts.12600
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author Xiao, Jim J.
Nowak, Dorota
Ramlau, Rodryg
Tomaszewska‐Kiecana, Monika
Wysocki, Piotr J.
Isaacson, Jeff
Beltman, Jeri
Nash, Eileen
Kaczanowski, Robert
Arold, Gerhard
Watkins, Simon
author_facet Xiao, Jim J.
Nowak, Dorota
Ramlau, Rodryg
Tomaszewska‐Kiecana, Monika
Wysocki, Piotr J.
Isaacson, Jeff
Beltman, Jeri
Nash, Eileen
Kaczanowski, Robert
Arold, Gerhard
Watkins, Simon
author_sort Xiao, Jim J.
collection PubMed
description This phase I study (CO‐338‐044; NCT02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly(ADP‐ribose) polymerase (PARP) inhibitor rucaparib on the pharmacokinetics (PK) of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P‐glycoprotein (P‐gp) substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg b.i.d. Geometric mean (GM) ratios (90% confidence interval (CI)) of area under the concentration‐time curve (AUC) from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2.26 (1.93–2.65); S‐warfarin, 1.49 (1.40–1.58); omeprazole, 1.55 (1.32–1.83); midazolam, 1.39 (1.14–1.68); and digoxin, 1.20 (1.12–1.29). There was limited effect on peak concentration of the substrates (GM ratios, 0.99–1.13). At steady state, rucaparib 600 mg b.i.d. moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and marginally increased digoxin exposure.
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spelling pubmed-63422422019-01-24 Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor Xiao, Jim J. Nowak, Dorota Ramlau, Rodryg Tomaszewska‐Kiecana, Monika Wysocki, Piotr J. Isaacson, Jeff Beltman, Jeri Nash, Eileen Kaczanowski, Robert Arold, Gerhard Watkins, Simon Clin Transl Sci Research This phase I study (CO‐338‐044; NCT02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly(ADP‐ribose) polymerase (PARP) inhibitor rucaparib on the pharmacokinetics (PK) of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P‐glycoprotein (P‐gp) substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg b.i.d. Geometric mean (GM) ratios (90% confidence interval (CI)) of area under the concentration‐time curve (AUC) from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2.26 (1.93–2.65); S‐warfarin, 1.49 (1.40–1.58); omeprazole, 1.55 (1.32–1.83); midazolam, 1.39 (1.14–1.68); and digoxin, 1.20 (1.12–1.29). There was limited effect on peak concentration of the substrates (GM ratios, 0.99–1.13). At steady state, rucaparib 600 mg b.i.d. moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and marginally increased digoxin exposure. John Wiley and Sons Inc. 2018-12-20 2019-01 /pmc/articles/PMC6342242/ /pubmed/30427584 http://dx.doi.org/10.1111/cts.12600 Text en © 2018 Clovis Oncology Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research
Xiao, Jim J.
Nowak, Dorota
Ramlau, Rodryg
Tomaszewska‐Kiecana, Monika
Wysocki, Piotr J.
Isaacson, Jeff
Beltman, Jeri
Nash, Eileen
Kaczanowski, Robert
Arold, Gerhard
Watkins, Simon
Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
title Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
title_full Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
title_fullStr Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
title_full_unstemmed Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
title_short Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
title_sort evaluation of drug–drug interactions of rucaparib and cyp1a2, cyp2c9, cyp2c19, cyp3a, and p‐gp substrates in patients with an advanced solid tumor
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342242/
https://www.ncbi.nlm.nih.gov/pubmed/30427584
http://dx.doi.org/10.1111/cts.12600
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