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kinase inhibitor, therapeutic drug monitoring, oncology

Pascaline Boudou-Rouquette, Camille Tlemsani, Benoit Blanchet, Olivier Huillard, Anne Jouinot, Jennifer Arrondeau, Audrey Thomas-Schoemann, Michel Vidal, Jérôme Alexandre, François Goldwasser
INTRODUCTION: In the past decade, treatment options for metastatic renal cell carcinoma and soft-tissue sarcoma have expanded. Pazopanib was discovered during the screening of compounds that suppressed vascular endothelial growth factor receptor-2 (VEGFR-2). As other tyrosine kinase inhibitors (TKI), pazopanib is not totally specific for one target since it also inhibits stem-cell factor receptor (cKIT), platelet-derived growth factor receptors (PDGFRα, β), VEGFR-1 and -3. AREAS COVERED: Clinical pharmacology, drug-drug interactions and safety data published on pazopanib, between January 2006 and April 2016, are reviewed...
August 24, 2016: Expert Opinion on Drug Metabolism & Toxicology
Pauline Herviou, Emilie Thivat, Damien Richard, Lucie Roche, Joyce Dohou, Mélanie Pouget, Alain Eschalier, Xavier Durando, Nicolas Authier
The therapeutic activity of drugs can be optimized by establishing an individualized dosage, based on the measurement of the drug concentration in the serum, particularly if the drugs are characterized by an inter-individual variation in pharmacokinetics that results in an under- or overexposure to treatment. In recent years, several tyrosine kinase inhibitors (TKIs) have been developed to block intracellular signaling pathways in tumor cells. These oral drugs are candidates for therapeutic drug monitoring (TDM) due to their high inter-individual variability for therapeutic and toxic effects...
August 2016: Oncology Letters
Thomas K Eigentler, Jessica C Hassel, Carola Berking, Jens Aberle, Oliver Bachmann, Viktor Grünwald, Katharina C Kähler, Carmen Loquai, Niels Reinmuth, Martin Steins, Lisa Zimmer, Anna Sendl, Ralf Gutzmer
PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment...
April 2016: Cancer Treatment Reviews
M Turjap, J Juřica, R Demlová
Imatinib mesylate is a competitive inhibitor of BCR/ ABL tyrosine kinase and inhibits also several receptor tyrosin kinases. Since its launch to the market, imatinib has proven to be very valuable in the treatment of Philadelphia chromosome (BCR/ ABL) -  positive (Ph+) chronic myeloid leukemia and Kit (CD117) positive gastrointestinal stromal tumors. The drug is metabolized by cytochrome P450, and there are many clinically important pharmacokinetic drug-drug interactions described in the literature. Frequent polypharmacy in oncological patients increases probability of such interactions, and also adherence may play its role during longterm treatment...
2015: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
Kathleen M Mahoney, Gordon J Freeman, David F McDermott
PURPOSE: Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma...
April 1, 2015: Clinical Therapeutics
Kuldeep Sharma, P S Suresh, Ramesh Mullangi, N R Srinivas
The introduction of small-molecule tyrosine kinase VEGFR2 (vascular endothelial growth factor receptor) inhibitors has added another dimension in the treatment of several oncology indications as they offer a unique mechanism. The VEGFR2 inhibitors have demonstrated superior benefits in treating certain types of cancer, such as renal cell carcinoma and hepatocellular carcinoma, as a monotherapy option. Many of the approved VEGFR2 inhibitors have also shown promise when used in combination with other anticancer agents...
June 2015: Biomedical Chromatography: BMC
M Pierobon, J Wulfkuhle, L Liotta, E Petricoin
The integration of small kinase inhibitors and monoclonal antibodies into oncological practice has opened a new paradigm for treating cancer patients. As proteins are the direct targets of the new generations of targeted therapeutics, many of which are kinase/enzymatic inhibitors, there is an increasing interest in developing technologies capable of monitoring post-translational changes of the human proteome for the identification of new predictive, prognostic and therapeutic biomarkers. It is well known that the vast majority of the activation/deactivation of these drug targets is driven by phosphorylation...
February 12, 2015: Oncogene
Markus Joerger
There is no personalized anticancer treatment without individualized dosing. Clearly, BSA-based chemotherapy dosing does not improve the substantial pharmacokinetic variability of individual drugs. Similarly, the new oral kinase inhibitors and endocrine compounds exhibit a marked pharmacokinetic variability due to variable absorption, hepatic metabolism and potential drug-drug and food-drug interactions. Therapeutic drug monitoring and genotyping may allow more individualized dosing of anticancer compounds in the future...
December 31, 2013: Praxis
Walter Emil Haefeli, Alexandra Carls
INTRODUCTION: Because 30 to 70% of tumour patients use complementary and alternative medicines; herb-drug combinations are particularly frequent in this population. Some of these combinations can critically alter exposure of anti-neoplastic and palliative treatment. AREAS COVERED: This review summarises pharmacokinetic drug interactions caused by the herbal products most frequently used by tumour patients (garlic, ginkgo, ginseng, echinacea and St John's wort [SJW])...
March 2014: Expert Opinion on Drug Metabolism & Toxicology
Susan Branford
Monitoring response to therapy for patients with chronic myeloid leukemia using an effective strategy is fundamental for achieving optimal patient outcomes. It will allow the initiation of timely therapeutic intervention for patients with a suboptimal response or kinase inhibitor therapy failure. Evidence is mounting that reaching molecular targets early in therapy is as important as the initial hematologic and cytogenetic response for the identification of patients who may have a poorer outcome. When the molecular target of a major molecular response is achieved at 18 months, patients reach a safe haven where loss of response is rare...
2012: Hematology—the Education Program of the American Society of Hematology
Laura Roca-Alonso, Loredana Pellegrino, Leandro Castellano, Justin Stebbing
Cardiotoxicity associated with breast cancer treatment is an important concern in the oncology clinic. Different types of anti-cancer therapies have recorded high rates of cardiac dysfunction in treated patients. Cardiac dysfunction linked to anthracyclines--one of the most common conventional chemotherapies--has extensively been described and several mechanisms have been proposed, although their mode of action is not fully understood even in cancer cells. The mediation of cardiac damage by reactive oxygen species stress is a recent hypothesis that has attracted a lot of interest, since it might explain the tissue-specific toxic effects of anthracyclines in the heart...
2012: Cardiology
Filip Razga, Tomas Jurcek, Daniela Zackova, Dana Dvorakova, Martina Toskova, Ivana Jeziskova, Jiri Mayer, Zdenek Racil
BACKGROUND AND OBJECTIVE: The availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables optimization of current therapeutic regimens; however, some patients lose their therapy response and acquire TKI resistance. In this study, we describe a single-center experience of monitoring BCR-ABL1 kinase domain (KD) mutations and discuss the impact of treatment on mutation selection. METHODS: Chronic myelogenous leukemia (CML) patients treated with TKIs at the Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno during 2003-2011 were included in this study...
August 1, 2012: Molecular Diagnosis & Therapy
Naifa L Busaidy, Azeez Farooki, Afshin Dowlati, John P Perentesis, Janet E Dancey, Laurence A Doyle, Joanna M Brell, Lillian L Siu
Agents inhibiting the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities...
August 10, 2012: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Elias Jabbour, Giuseppe Saglio, Timothy P Hughes, Hagop Kantarjian
The high response rates and increased survival associated with imatinib therapy prompted a paradigm shift in the management of chronic myeloid leukemia. However, 25% to 30% of imatinib-treated patients develop drug resistance or intolerance, increasing the risk of disease progression and poor prognosis. In 2006, the European LeukemiaNet proposed criteria to identify patients with a suboptimal response to, or failure associated with, imatinib; these recommendations were updated in 2009. Suboptimal responders represent a unique treatment challenge...
March 1, 2012: Cancer
Siu-Fun Wong, Hamid Mirshahidi
OBJECTIVE: To summarize the use of tyrosine kinase inhibitors (TKIs) for treatment of patients with chronic myeloid leukemia (CML) and provide practical information for patient management. DATA SOURCES: Literature was retrieved from PubMed (2000-January 2011), using the search terms chronic myeloid leukemia and tyrosine kinase inhibitor. Abstracts presented at the 2008-2010 annual meetings of the American Society of Hematology and the American Society of Clinical Oncology, reference citations from identified publications, as well as the manufacturers' full prescribing information for cited drugs, also were reviewed...
June 2011: Annals of Pharmacotherapy
A A Leitner, R Hehlmann
Chronic myeloid leukemia (CML) is exceptional amongst neoplasias since its underlying pathomechanism has been elucidated, and potent well tolerated targeted drugs, the tyrosine kinase inhibitors (TKI), are available for treatment. They convincingly improve prognosis while retaining good quality of life. Aims of therapy are complete remissions as well as prolongation of life and cure. Imatinib 400 mg per day is current standard therapy. There are hints for a better outcome with a higher initial imatinib dose or with combination therapy...
February 2011: Der Internist
N T Ihle, G Powis, S Kopetz
Despite recent successes, metastatic colorectal cancer remains a difficult cancer to treat. Since the initial discovery that PI-3-Kinase/AKT signaling played an important part in the growth and survival of colorectal tumors, preclinical studies have suggested that inhibitors of this pathway may have a role to play as potential therapeutics. With the surge of inhibitors of PI-3-Kinase from both academia and pharmaceutical companies rapidly moving through early clinical trials, the question of whether these preclinical studies will translate to patients will soon be answered...
February 2011: Current Cancer Drug Targets
Stéphane Bouchet, Bernard Royer, Chantal Le Guellec, Karine Titier et al.
During the last decade, imatinib was current gold standard treatment of chronic myelogenous leukemia (CML), showing a great effectiveness. Thus, the Therapeutic Drug Monitoring (TDM), rarely applied in clinical oncology practice, did not appear necessary at the moment. However, the absence of response among patients and the metabolic profile of imatinib (involving the CYP3A4) suggested the existence of a great interindividual variability. During the last 4 years, studies about the pharmacokinetic/pharmacodynamic relationship have confirmed this variability and highlighted a relation between the trough concentrations of imatinib and the clinical response...
May 2010: Thérapie
Laura S Wood
Treatment options for renal cell carcinoma have changed dramatically since 2005 when the U.S. Food and Drug Administration approved six new therapies. These agents inhibit pathways relevant in the pathogenesis of renal cell carcinoma, interfering with tumor angiogenesis, cell progression, and metastasis. Understanding the pharmacology of these agents is necessary for clinicians to provide appropriate patient education, assure adherence with the treatment plan, and facilitate early identification and intervention for side effects...
January 2010: Urologic Nursing
Meihong Deng, Hai Huang, Hao Jin, Olaf Dirsch, Uta Dahmen
BACKGROUND: Blocking of EGFR signaling by the tyrosine kinase inhibitor AEE788 was well tolerated and did not inhibit liver regeneration after standard 70% partial hepatectomy (PH) in a rat model, as demonstrated previously. However, serum levels of AEE788 at POW1 were 3-fold higher than in the non-resected control group. Therefore, we expanded theses studies to a model of extended 90%PH to investigate the role of liver size for the metabolism of AEE788 and its potential influence on side effects, liver regeneration and liver remodeling...
August 2011: Investigational New Drugs
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