Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies

Clinical Pharmacokinetics
Elodie OdoreKeyvan Rezaï

Abstract

OTX015 (MK-8628) is a novel inhibitor of the bromodomain and extraterminal (BET)-bromodomain (BRD) protein family, binding specifically to bromodomains BRD2/3/4 and impacting the epigenetic regulation of several oncogenes. We characterized the pharmacokinetics of this first-in-class BET-BRD inhibitor administered as a single agent, including population pharmacokinetic modelling. A dose-escalation, phase Ib study was performed with oral OTX015 in patients with haematologic malignancies, at doses starting from 10 mg once daily (QD) with continuous or discontinuous schedules. Five or eight blood samples were collected per patient for pharmacokinetic analysis. OTX015 plasma concentrations were determined using validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and analysed using a nonlinear mixed-effects modelling software program. A population pharmacokinetic model was fitted to the data, and patient demographics and clinical chemistry parameters were tested as predictive covariates on the model parameters. Blood samples were analysed from 81 patients treated with OTX015 at doses ranging from 10 to 160 mg QD or 40 mg twice daily (BID), and 633 time-plasma concentrations were available for analy...Continue Reading

References

Jan 1, 1981·Pharmacology & Therapeutics·J G Wagner
Feb 1, 1996·Clinical Pharmacokinetics·S VozehL Aarons
Dec 19, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lena E FribergMats O Karlsson
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Sep 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jennifer A MertzRobert J Sims
May 31, 2012·The Journal of Biological Chemistry·Guangtao ZhangMing-Ming Zhou
Feb 14, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zhixiang ChengJialiang Wang
Sep 21, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Takeshi ShimamuraKwok-Kin Wong
Jan 28, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michela BoiFrancesco Bertoni

❮ Previous
Next ❯

Citations

Jun 14, 2016·Current Opinion in Chemical Biology·Natalie H TheodoulouPhilip G Humphreys
Sep 7, 2016·International Journal of Cancer. Journal International Du Cancer·Ramiro VázquezRoberta Frapolli
Apr 14, 2016·Scientific Reports·Panpan LuHuanzhang Zhu
May 26, 2017·Expert Opinion on Investigational Drugs·Thorsten Braun, Claude Gardin
Nov 28, 2016·Hematology/oncology Clinics of North America·Pierre SujobertEmmanuel Bachy
Nov 13, 2018·Journal of Cellular Biochemistry·Susu ZhangScott W Hiebert
Oct 30, 2016·Oncotarget·Michela BoiUNKNOWN AIRC 5xMille Consortium ‘Genetics-Driven Targeted Management of Lymphoid Malignancies’
Jul 4, 2019·Investigational New Drugs·Mohammadali Soleimani DamanehYing-Qing Wang
Dec 3, 2016·Pediatric Blood & Cancer·Irene JiménezJohannes Schulte
Apr 14, 2018·EMBO Molecular Medicine·Ileabett M Echevarría-VargasJessie Villanueva
Feb 16, 2019·Nature Reviews. Urology·Sina JostesHubert Schorle
Nov 1, 2018·Current Medicinal Chemistry·Victoria Lucia AlonsoEsteban Serra
Jul 9, 2016·International Journal of Cancer. Journal International Du Cancer·Caroline Berenguer-DaizéL'Houcine Ouafik
Jul 6, 2019·Nature Reviews. Drug Discovery·Andrea G CochranRobert J Sims
Jun 3, 2020·The Biochemical Journal·Prashant DeshmukhBalasundaram Padmanabhan
May 8, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jeremy LewinChristophe Massard
Nov 10, 2020·Leukemia & Lymphoma·Natalie Cheng ChenNaveen Pemmaraju
Jan 24, 2018·Cancer Discovery·David S RickmanMartin Eilers
Jul 22, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xuguang ZhuSheue-Yann Cheng
Feb 18, 2017·Cancer Research·Longchuan BaiShaomeng Wang
Dec 4, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anton HenssenJohannes H Schulte
Mar 17, 2019·Cancer Research·Tatiana ShorstovaMichael Witcher
Nov 17, 2020·Bioorganic & Medicinal Chemistry·Yifei YangJinpei Zhou
Mar 7, 2021·International Journal of Molecular Sciences·Tiziana ServideiRiccardo Riccardi
Feb 19, 2021·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Andrew Dj PearsonGilles Vassal
Apr 22, 2018·Bioorganic & Medicinal Chemistry Letters·Steven D FidanzeKeith F McDaniel
Mar 17, 2021·British Journal of Cancer·Tatiana ShorstovaMichael Witcher
Apr 13, 2021·Journal of Biomedical Science·Kunal Nepali, Jing-Ping Liou
Jul 25, 2021·Cancers·Samuel P BoysonKaren C Glass
Aug 11, 2021·Journal of Hematology & Oncology·Seyed Esmaeil AhmadiMajid Safa
Feb 7, 2018·Chemical Reviews·Ibraheem AliMelanie Ott
Aug 31, 2021·RSC Chemical Biology·Robert B A Quinlan, Paul E Brennan

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
S H IngwersenL Aarons
Antimicrobial Agents and Chemotherapy
Jongtae LeeDong-Seok Yim
Antimicrobial Agents and Chemotherapy
Suzanne L ParkerJason A Roberts
Journal of Veterinary Pharmacology and Therapeutics
D H ZhaoY H Liu
© 2021 Meta ULC. All rights reserved