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Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated...

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Autores principales: Ogasawara, Ken, MacGorman, Kimberly, Liu, Liangang, Chen, Jian, Carayannopoulos, Leonidas N., Zhou, Simon, Palmisano, Maria, Li, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851786/
https://www.ncbi.nlm.nih.gov/pubmed/31172535
http://dx.doi.org/10.1002/jcph.1453
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author Ogasawara, Ken
MacGorman, Kimberly
Liu, Liangang
Chen, Jian
Carayannopoulos, Leonidas N.
Zhou, Simon
Palmisano, Maria
Li, Yan
author_facet Ogasawara, Ken
MacGorman, Kimberly
Liu, Liangang
Chen, Jian
Carayannopoulos, Leonidas N.
Zhou, Simon
Palmisano, Maria
Li, Yan
author_sort Ogasawara, Ken
collection PubMed
description Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC(0‐inf)) and maximum observed plasma concentration (C(max)), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC(0‐inf) and C(max), respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC(0‐inf) and C(max), respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.
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spelling pubmed-68517862019-11-18 Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects Ogasawara, Ken MacGorman, Kimberly Liu, Liangang Chen, Jian Carayannopoulos, Leonidas N. Zhou, Simon Palmisano, Maria Li, Yan J Clin Pharmacol Drug Interactions Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC(0‐inf)) and maximum observed plasma concentration (C(max)), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC(0‐inf) and C(max), respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC(0‐inf) and C(max), respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin. John Wiley and Sons Inc. 2019-06-06 2019-12 /pmc/articles/PMC6851786/ /pubmed/31172535 http://dx.doi.org/10.1002/jcph.1453 Text en © 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. 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-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 Drug Interactions
Ogasawara, Ken
MacGorman, Kimberly
Liu, Liangang
Chen, Jian
Carayannopoulos, Leonidas N.
Zhou, Simon
Palmisano, Maria
Li, Yan
Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
title Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
title_full Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
title_fullStr Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
title_full_unstemmed Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
title_short Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
title_sort drug‐drug interaction study to assess the effect of cytochrome p450 inhibition and induction on the pharmacokinetics of the novel cereblon modulator avadomide (cc‐122) in healthy adult subjects
topic Drug Interactions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851786/
https://www.ncbi.nlm.nih.gov/pubmed/31172535
http://dx.doi.org/10.1002/jcph.1453
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