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9 results on '"Cleary, Yumi"'

2. A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier

Author

Sturm, Stefan, primary, Günther, Andreas, additional, Jaber, Birgit, additional, Jordan, Paul, additional, Al Kotbi, Nada, additional, Parkar, Nikhat, additional, Cleary, Yumi, additional, Frances, Nicolas, additional, Bergauer, Tobias, additional, Heinig, Katja, additional, Kletzl, Heidemarie, additional, Marquet, Anne, additional, Ratni, Hasane, additional, Poirier, Agnès, additional, Müller, Lutz, additional, Czech, Christian, additional, and Khwaja, Omar, additional

Published
2018
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5. Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective

Author

Shebley, Mohamad, primary, Sandhu, Punam, additional, Emami Riedmaier, Arian, additional, Jamei, Masoud, additional, Narayanan, Rangaraj, additional, Patel, Aarti, additional, Peters, Sheila Annie, additional, Reddy, Venkatesh Pilla, additional, Zheng, Ming, additional, de Zwart, Loeckie, additional, Beneton, Maud, additional, Bouzom, Francois, additional, Chen, Jun, additional, Chen, Yuan, additional, Cleary, Yumi, additional, Collins, Christiane, additional, Dickinson, Gemma L., additional, Djebli, Nassim, additional, Einolf, Heidi J., additional, Gardner, Iain, additional, Huth, Felix, additional, Kazmi, Faraz, additional, Khalil, Feras, additional, Lin, Jing, additional, Odinecs, Aleksandrs, additional, Patel, Chirag, additional, Rong, Haojing, additional, Schuck, Edgar, additional, Sharma, Pradeep, additional, Wu, Shu-Pei, additional, Xu, Yang, additional, Yamazaki, Shinji, additional, Yoshida, Kenta, additional, and Rowland, Malcolm, additional

Published
2018
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8. Model-Based Assessments of CYP-Mediated Drug-Drug Interaction Risk of Alectinib: Physiologically Based Pharmacokinetic Modeling Supported Clinical Development.

Author

Cleary Y, Gertz M, Morcos PN, Yu L, Youdim K, Phipps A, Fowler S, and Parrott N

Subjects
Activation, Metabolic, Carbazoles adverse effects, Cytochrome P-450 CYP2C8 Inhibitors adverse effects, Cytochrome P-450 CYP2C8 Inhibitors pharmacokinetics, Cytochrome P-450 CYP3A Inhibitors adverse effects, Cytochrome P-450 CYP3A Inhibitors pharmacokinetics, Drug Approval, Drug Interactions, Humans, Patient Safety, Piperidines adverse effects, Protein Kinase Inhibitors adverse effects, Risk Assessment, Substrate Specificity, United States, United States Food and Drug Administration, Carbazoles pharmacokinetics, Computer Simulation, Cytochrome P-450 CYP2C8 metabolism, Cytochrome P-450 CYP3A metabolism, Drug Development methods, Models, Biological, Piperidines pharmacokinetics, Protein Kinase Inhibitors pharmacokinetics
Abstract

Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfill the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was made to ensure extrapolation ability of DDI risk. The PBPK modeling has provided mechanistic insight into the low victim DDI risk of alectinib through CYP3A4 by a novel two-dimensional analysis for fm CYP3A4 and F G , and demonstrated negligible CYPs 2C8 and 3A4 enzyme-modulating effects at clinically relevant exposure. This work supports that alectinib can be prescribed without dose adjustment for CYP-mediated DDI liabilities., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Published
2018
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9. Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.

Author

Morcos PN, Cleary Y, Guerini E, Dall G, Bogman K, De Petris L, Viteri S, Bordogna W, Yu L, Martin-Facklam M, and Phipps A

Subjects
Adult, Anaplastic Lymphoma Kinase, Carbazoles administration & dosage, Carcinoma, Non-Small-Cell Lung genetics, Cytochrome P-450 CYP3A metabolism, Dose-Response Relationship, Drug, Female, Humans, Lung Neoplasms genetics, Male, Midazolam pharmacology, Middle Aged, Piperidines administration & dosage, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases genetics, Rifampin pharmacology, Treatment Outcome, Triazoles pharmacology, Young Adult, Carbazoles pharmacokinetics, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Midazolam administration & dosage, Piperidines pharmacokinetics, Rifampin administration & dosage, Triazoles administration & dosage
Abstract

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates., (© 2016, The American College of Clinical Pharmacology.)

Published
2017
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