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Lewis L, Thompson B, Stellmaker R, Koelmeyer L. Body composition and chemotherapy toxicities in breast cancer: a systematic review of the literature. J Cancer Surviv 2025; 19:914-929. [PMID: 38206431 PMCID: PMC12081505 DOI: 10.1007/s11764-023-01512-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024]
Abstract
PURPOSE Breast cancer is the most diagnosed cancer in women with chemotherapy being a common treatment. Toxicities due to chemotherapy can result in dose reduction, delay, and early cessation of treatment, which along with causing distress for individuals during their cancer treatment might also reduce the therapeutic effect. The purpose of this systematic review is to examine the role of body composition on chemotherapy toxicities in women with breast cancer. METHODS A systematic search of the literature was completed on electronic databases Pubmed, Embase, CINHAHL, and Cochrane. Studies were included if the direct effect of body composition on chemotherapy toxicities was reported and excluded if body composition could not be isolated. A critical appraisal of the studies included was performed using McMasters University Critical Review Form for Quantitative Studies. RESULTS Eleven studies were included with a total of 2881 female participants. All studies reported significant relationships between body composition and chemotherapy toxicities; however, individual parameters differed between the studies. Adding to the heterogeneity, different thresholds were reported to determine both sarcopenia and myosteatosis, making it difficult to identify a common finding. CONCLUSION This review suggests that body composition may be an important factor in predicting the severity of chemotherapy toxicities during treatment for breast cancer; however, the lack of international consensus as to thresholds in the literature for sarcopenia and myosteatosis may result in bias. The review supports the need for further prospective studies, allowing for more robust, pre-determined data collection, to better understand the implications of body composition on toxicities and benefits of using body composition to individualize chemotherapy dosing. IMPLICATIONS FOR CANCER SURVIVORS Toxicities due to chemotherapy can result in treatment being unable to be completed as planned, potentially resulting in poorer survival outcomes. Improved knowledge in this area may give rise to a more reliable way of individualizing chemotherapy dosage to help mitigate this risk.
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Affiliation(s)
- Lori Lewis
- Australian Lymphoedema Education, Research & Treatment (ALERT) Program, Department of Health Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia.
| | - Belinda Thompson
- Australian Lymphoedema Education, Research & Treatment (ALERT) Program, Department of Health Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Rhiannon Stellmaker
- Australian Lymphoedema Education, Research & Treatment (ALERT) Program, Department of Health Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Louise Koelmeyer
- Australian Lymphoedema Education, Research & Treatment (ALERT) Program, Department of Health Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 75 Talavera Road, Sydney, NSW, 2109, Australia
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2
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Agema BC, Koch BCP, Mathijssen RHJ, Koolen SLW. From Prospective Evaluation to Practice: Model-Informed Dose Optimization in Oncology. Drugs 2025; 85:487-503. [PMID: 39939511 PMCID: PMC11946950 DOI: 10.1007/s40265-025-02152-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2025] [Indexed: 02/14/2025]
Abstract
One dose does not fit all, especially in oncolytic drugs, where side effects and therapy failures highlight the need for personalized dosing approaches. In recent years, the quest to apply model-informed precision dosing to oncology drugs has gained significant momentum, reflecting its potential to revolutionize patient care by tailoring treatments to individual pharmacokinetic profiles. Despite this progress, model-informed precision dosing has not (yet) become widely integrated into routine clinical care. We aimed to explain model-informed precision dosing from a clinical viewpoint while addressing all prospective model-informed precision dosing implementation and validation studies in the field of oncology. We identified 16 different drugs for which prospective model-informed precision dosing validation/implementation has been performed. Although these studies are mostly focused on attaining adequate drug exposures and reducing inter-individual variability, improved clinical outcomes after performing model-informed precision dosing were shown for busulfan, and high-dose methotrexate. Toxicities were significantly reduced for busulfan and cyclophosphamide treatment. In contrast, for carboplatin, for which model-informed precision dosing has been used in the Calvert formula, no prospective validation on outcomes was deemed necessary as the therapeutic window had been extensively validated. Model-informed precision dosing has shown to be of added value in oncology and is expected to significantly change dosing regimens in the future.
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Affiliation(s)
- Bram C Agema
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands.
| | - Birgit C P Koch
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Stijn L W Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
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Radhakrishnan H, Newmyer SL, Javitz HS, Bhatnagar P. Engineered CD4 T cells for in vivo delivery of therapeutic proteins. Proc Natl Acad Sci U S A 2024; 121:e2318687121. [PMID: 39312667 PMCID: PMC11459198 DOI: 10.1073/pnas.2318687121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
The CD4 T cell, when engineered with a chimeric antigen receptor (CAR) containing specific intracellular domains, has been transformed into a zero-order drug-delivery platform. This introduces the capability of prolonged, disease-specific engineered protein biologics production, at the disease site. Experimental findings demonstrate that CD4 T cells offer a solution when modified with a CAR that includes 4-1BB but excludes CD28 intracellular domain. In this configuration, they achieve ~3X transduction efficiency of CD8 T cells, ~2X expansion rates, generating ~5X more biologic, and exhibit minimal cytolytic activity. Cumulatively, this addresses two main hurdles in the translation of cell-based drug delivery: scaling the production of engineered T cell ex vivo and generating sufficient biologics in vivo. When programmed to induce IFNβ upon engaging the target antigen, the CD4 T cells outperforms CD8 T cells, effectively suppressing cancer cell growth in vitro and in vivo. In summary, this platform enables precise targeting of disease sites with engineered protein-based therapeutics while minimizing healthy tissue exposure. Leveraging CD4 T cells' persistence could enhance disease management by reducing drug administration frequency, addressing critical challenges in cell-based therapy.
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Radhakrishnan H, Newmyer SL, Ssemadaali MA, Javitz HS, Bhatnagar P. Primary T-cell-based delivery platform for in vivo synthesis of engineered proteins. Bioeng Transl Med 2024; 9:e10605. [PMID: 38193126 PMCID: PMC10771566 DOI: 10.1002/btm2.10605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/12/2023] [Accepted: 09/18/2023] [Indexed: 01/10/2024] Open
Abstract
Primary T cell has been transformed into a cell-based delivery platform that synthesizes complex biologics at the disease site with spatiotemporal resolution. This broadly applicable technology can circumvent toxicities due to systemic administration of biologics that necessitates the use of high doses and may diffuse to the healthy tissues. Its clinical translation, however, has been impeded by manufacturing bottlenecks. In this work, a range of process parameters were investigated for increasing the production yield of the primary T cells engineered for delivery function. Compared to the common spinoculation-based method, the transduction yield was enhanced ~2.5-fold by restricting the transduction reaction volume for maximizing the lentivector-to-T-cell contact. Cell density and cytokines used in the expansion process were adjusted to achieve >100-fold expansion of the T-cell-based delivery platform in 14 days, and the function of these cells was validated in vivo using intraperitoneally implanted tumor cells. The primary T-cell-based delivery platform has human applications because it can be scaled and administrated to express a broad range of therapeutic proteins (e.g., cytokines, interferons, enzymes, agonists, and antagonists) at the disease site, obviating the need for systemic delivery of large doses of these proteins.
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5
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Zamboni WC, Charlab R, Burckart GJ, Stewart CF. Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents. J Clin Pharmacol 2023; 63 Suppl 2:S85-S102. [PMID: 37942904 DOI: 10.1002/jcph.2326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/12/2023] [Indexed: 11/10/2023]
Abstract
An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.
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Affiliation(s)
- William C Zamboni
- UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Caroline Institute of Nanomedicine, University of North Carolina, Chapel Hill, NC, USA
| | - Rosane Charlab
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Gilbert J Burckart
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
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da Silva LC, Grando AP, de Baco LS, Hahn RZ, Ferreira Filho AF, Brucker N, Linden R, Antunes MV. Evaluation of dried blood spots as an alternative sampling strategy for 5-fluorouracil monitoring: From method development to clinical application. J Pharm Biomed Anal 2023; 235:115539. [PMID: 37517245 DOI: 10.1016/j.jpba.2023.115539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 06/01/2023] [Accepted: 06/18/2023] [Indexed: 08/01/2023]
Abstract
Therapeutic drug monitoring (TDM) of 5-Fluorouracil (5-FU) is strongly recommended because of its large inter-individual pharmacokinetic variability, narrow therapeutic window, and incidence of toxicity. However, there are several factors that limit the application of TDM in clinical settings. Considering the intrinsic advantages of dried microsamples, such as minimally invasive sampling, analyte stability, and cost-effective logistics, this study aimed to develop a method for the determination of 5-FU in dried blood spots (DBS) using ultra-high liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and to evaluate its clinical application. Sample preparation was based on an aqueous extraction followed by protein precipitation. Separation was performed in an Acquity UPLC® HSS C18 (150 ×2.1 mm, 1.8 µm), and the mobile phases were water and acetonitrile with 0.5% acetic acid. The total run time was 5.5 min. The method was linear from 100 to 2000 ng/mL, precise (maximum CV% of 7.5%), and accurate (98.3-115.4%). The average recovery was 70%. Blood hematocrit had a minimal impact on the assay. DBS samples were stable for 21 days at 4, 25, and 45 °C. A total of 40 paired samples of plasma, capillary DBS, and venous DBS were analyzed. Median 5-FU concentrations were 444.7, 637.0, and 499.7 ng/mL for plasma, capillary DBS, and venous DBS, respectively. Capillary and plasma concentrations were significantly correlated (r > 0.90), but there was a lack of agreement between the methods, as capillary DBS levels were on average 146% of plasma. Venous DBS corresponded to 110% of the measured plasma concentrations, with a strong correlation (r > 0.97) and agreement between the methods. Our study is the first to report the use of DBS samples to quantify 5-FU. Further studies are needed to establish whether capillary samples can replace plasma.
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Affiliation(s)
- Laura C da Silva
- Graduate Program on Toxicology and Analytical Toxicology, Feevale University, Novo Hamburgo, RS, Brazil; Toxicological Analysis Laboratory, Institute of Health Sciences, Feevale University, Novo Hamburgo, RS, Brazil.
| | - Ana P Grando
- Toxicological Analysis Laboratory, Institute of Health Sciences, Feevale University, Novo Hamburgo, RS, Brazil
| | | | - Roberta Z Hahn
- Toxicological Analysis Laboratory, Institute of Health Sciences, Feevale University, Novo Hamburgo, RS, Brazil
| | | | | | - Rafael Linden
- Graduate Program on Toxicology and Analytical Toxicology, Feevale University, Novo Hamburgo, RS, Brazil; Toxicological Analysis Laboratory, Institute of Health Sciences, Feevale University, Novo Hamburgo, RS, Brazil
| | - Marina V Antunes
- Graduate Program on Toxicology and Analytical Toxicology, Feevale University, Novo Hamburgo, RS, Brazil; Toxicological Analysis Laboratory, Institute of Health Sciences, Feevale University, Novo Hamburgo, RS, Brazil
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He JZ, Wang H, Lim K, Ren S, Rollins F, Vallaster M, Wong R, Stebbings R, Standifer N, Keefe R, Phipps A, Gibbs M. A Consideration of Fixed Dosing Versus Body Size-Based Dosing Strategies for Chimeric Antigen Receptor T-Cell Therapies. Clin Pharmacol Drug Dev 2022; 11:1130-1135. [PMID: 36094760 PMCID: PMC9826131 DOI: 10.1002/cpdd.1171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/19/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Jimmy Zhijian He
- Clinical Pharmacology and Quantitative PharmacologyBiopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
| | - Hechuan Wang
- Clinical Pharmacology and Quantitative PharmacologyBiopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
| | - KyoungSoo Lim
- Clinical Pharmacology and Quantitative PharmacologyBiopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
| | - Song Ren
- Clinical Pharmacology and Quantitative PharmacologyBiopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
| | - Fred Rollins
- Competitive Intelligence and AnalysisOncology R&D, AstraZenecaGaithersburgMarylandUSA
| | - Markus Vallaster
- Clinical DevelopmentCell Therapies and Immuno‐Oncology, AstraZenecaWalthamMassachusettsUSA
| | - Ryan Wong
- Clinical Pharmacology and Safety SciencesBiopharmaceuticals R&D, AstraZenecaCambridgeUK
| | - Richard Stebbings
- Clinical Pharmacology and Safety SciencesBiopharmaceuticals R&D, AstraZenecaCambridgeUK
| | - Nathan Standifer
- Integrated BioanalysisClinical Pharmacology and Safety SciencesBiopharmaceuticals R&D, AstraZenecaSouth San FranciscoCaliforniaUSA
| | - Robert Keefe
- CMC DevelopmentCell Therapy, Oncology R&D, AstraZenecaGaithersburgMarylandUSA
| | - Alex Phipps
- Clinical Pharmacology and Quantitative PharmacologyBiopharmaceuticals R&D, AstraZenecaCambridgeUK
| | - Megan Gibbs
- Clinical Pharmacology and Quantitative PharmacologyBiopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
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8
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Nuvvula S, Dahiya S, Patel SA. The Novel Therapeutic Landscape for Relapsed/Refractory Diffuse Large B Cell Lymphoma. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:362-372. [PMID: 34922844 DOI: 10.1016/j.clml.2021.11.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/06/2021] [Accepted: 11/14/2021] [Indexed: 12/12/2022]
Abstract
Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy that has been traditionally treated with anthracycline-based chemotherapy, but approximately one-third of patients relapse after first-line therapy or have primary refractoriness. In this focused review, we discuss the 7 novel Food & Drug Administration (FDA)-approved medications for relapsed/refractory (R/R) DLBCL. We describe 5 CD19-targeted therapies, 3 of which are chimeric antigen receptor (CAR)-T cell therapies. We also highlight novel non-cell-based targeted therapies and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on CAR-T cell therapy as curative intent. We consider the limited tolerability of certain novel agents, prospects for elderly patients, and financial aspects of these approaches. We discuss advantages and limitations of these targeted therapies based on seminal clinical trials. Finally, we summarize ongoing trials involving promising agents making their way into the pharmacologic pipeline. These therapies include allogeneic CAR-T treatments and multi-antigen targeting therapies such as the CD19/CD22 CAR-T and the CD3/CD20 bispecific antibodies mosunetuzumab and odronextamab. We summarize our approach based on the best available evidence as we enter 2022.
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Affiliation(s)
- Sri Nuvvula
- Department of Medicine - Division of Hematology/Oncology, University of Massachusetts Chan Medical School, UMass Memorial Medical Center, Worcester, MA
| | - Saurabh Dahiya
- Department of Medicine - Division of Hematology/Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD
| | - Shyam A Patel
- Department of Medicine - Division of Hematology/Oncology, University of Massachusetts Chan Medical School, UMass Memorial Medical Center, Worcester, MA.
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Skubitz KM, Lindgren BR, Domingo-Musibay E, Cheng EY. Prospective Trial of Monocyte Count as a Biomarker of Hand-Foot Syndrome Among Patients With Soft Tissue Sarcomas Treated With Pegylated Liposomal Doxorubicin and Ifosfamide. Cureus 2022; 14:e24498. [PMID: 35651410 PMCID: PMC9135613 DOI: 10.7759/cureus.24498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2022] [Indexed: 11/05/2022] Open
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Schmulenson E, Zimmermann N, Mikus G, Joerger M, Jaehde U. Current status and future outlooks on therapeutic drug monitoring of fluorouracil. Expert Opin Drug Metab Toxicol 2022; 17:1407-1422. [PMID: 35029518 DOI: 10.1080/17425255.2021.2029403] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION : Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied. AREAS COVERED : This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine. EXPERT OPINION : New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Pre-emptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.
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Affiliation(s)
- Eduard Schmulenson
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Nigina Zimmermann
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Gerd Mikus
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany.,Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.,Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus Joerger
- Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Ulrich Jaehde
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
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11
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Bril SI, Al-Mamgani A, Chargi N, Remeijer P, Devriese LA, de Boer JP, de Bree R. The association of pretreatment low skeletal muscle mass with chemotherapy dose-limiting toxicity in patients with head and neck cancer undergoing primary chemoradiotherapy with high-dose cisplatin. Head Neck 2021; 44:189-200. [PMID: 34713519 PMCID: PMC9298001 DOI: 10.1002/hed.26919] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 10/01/2021] [Accepted: 10/18/2021] [Indexed: 12/25/2022] Open
Abstract
Background Low skeletal muscle mass (SMM) is an adverse prognostic factor for chemotherapy dose‐limiting toxicity (CDLT). In patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), low SMM is a predictor for CDLT. We aimed to validate these findings. Methods Consecutive LA‐HNSCC patients treated with primary CRT with high‐dose cisplatin were retrospectively included. SMM was measured on pre‐treatment CT‐imaging. A cumulative cisplatin dose below 200 mg/m2 was defined as CDLT. Results One hundred and fifty three patients were included; 37 (24.2%) experienced CDLT, and 84 had low SMM (54.9%). Patients with low SMM experienced more CDLT than patients with normal SMM (35.7% vs. 10.1%, p < 0.01). Low SMM (OR 3.99 [95% CI 1.56–10.23], p = 0.01) and an eGFR of 60–70 ml/min (OR 5.40 [95% CI 1.57–18.65], p < 0.01) were predictors for CDLT. Conclusion Pre‐treatment low SMM is associated with CDLT in LA‐HNSCC patients treated with primary CRT. Routine SMM assessment may allow for CDLT risk assessment and treatment optimization.
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Affiliation(s)
- Sandra I Bril
- Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Abrahim Al-Mamgani
- Department of Radiation Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - Najiba Chargi
- Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Peter Remeijer
- Department of Radiation Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - Lot A Devriese
- Department of Medical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jan Paul de Boer
- Department of Medical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - Remco de Bree
- Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands
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12
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Clarke WA, Chatelut E, Fotoohi AK, Larson RA, Martin JH, Mathijssen RHJ, Salamone SJ. Therapeutic drug monitoring in oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology consensus guidelines for imatinib therapy. Eur J Cancer 2021; 157:428-440. [PMID: 34597977 DOI: 10.1016/j.ejca.2021.08.033] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/17/2021] [Accepted: 08/19/2021] [Indexed: 12/30/2022]
Abstract
Although therapeutic drug monitoring (TDM) is an important tool in guiding drug dosing for other areas of medicine including infectious diseases, cardiology, psychiatry and transplant medicine, it has not gained wide acceptance in oncology. For imatinib and other tyrosine kinase inhibitors, a flat dosing approach is utilised for management of oral chemotherapy. There are many published studies examining the correlation of blood concentrations with clinical effects of imatinib. The International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) determined that there was a need to examine the published literature regarding utility of TDM in imatinib therapy and to develop consensus guidelines for TDM based on the available data. This article summarises the scientific evidence regarding TDM of imatinib, as well as the consensus guidelines developed by the IATDMCT.
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Affiliation(s)
- William A Clarke
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Etienne Chatelut
- Université de Toulouse, Inserm, Institut Claudius-Regaud, Toulouse, France
| | - Alan K Fotoohi
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Huddinge, Stockholm, 141 86, Sweden
| | - Richard A Larson
- Department of Medicine and Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA
| | - Jennifer H Martin
- Centre for Drug Repurposing and Medicines Research, University of Newcastle. Level 3, Hunter Medical Research Institute, New Lambton Heights, 2305, New South Wales, Australia. https://twitter.com/jenhelenmar
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
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Youn S, Chen A, Ha V, Chambers C, Eurich DT, McCall M, Sawyer MB. An exploratory study of body composition as a predictor of dose-limiting toxicity in metastatic pancreatic cancer treated with gemcitabine plus nab-paclitaxel. Clin Nutr 2021; 40:4888-4892. [PMID: 34358833 DOI: 10.1016/j.clnu.2021.06.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/29/2021] [Accepted: 06/24/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Body composition is increasingly being studied as a method of predicting chemotherapy toxicity. Our study aimed to evaluate associations of body composition with treatment toxicity in a group of pancreatic cancer patients treated with gemcitabine plus nab-paclitaxel. METHODS A retrospective review was performed for all patients who received first-line gemcitabine plus nab-paclitaxel for metastatic pancreatic cancer at a northern Alberta cancer institute (Canada) from 2014 to 2017. Total lean body mass (LBM) was derived from measurements of muscle surface area at L3 on baseline computed tomography (CT) scans. Optimal stratification, or minimal p-value analysis, was used to assess for a threshold of nab-paclitaxel dose per LBM (mg/kg) associated with a higher risk of dose-limiting toxicity (DLT). RESULTS 152 patients were included in the study, of whom 62 (40.8%) experienced DLT. nab-Paclitaxel dose/LBM ranged from 0.98 to 8.76 mg/kg. A threshold for nab-paclitaxel dose/LBM that optimally predicted risk of DLT was identified at 5.83 mg/kg. Above this cut-off, 18/31 (58.1%) patients experienced DLT, compared to 44/121 (36.4%) patients below (p = 0.028). Patients above this cut-off had a higher incidence of peripheral neuropathy compared to those below, though this was not statistically significant based on an adjusted p-value threshold (48.4 vs. 29.8% respectively, p = 0.050). Body mass index, body surface area, and absolute initial doses of nab-paclitaxel or gemcitabine did not significantly impact likelihood of DLT. CONCLUSIONS nab-Paclitaxel dose normalized to LBM, based on CT-derived measures of skeletal muscle, has potential to predict risk of chemotherapy toxicity. Chemotherapy dosing based on body composition, rather than conventional anthropometric measures, may be effective in reducing treatment toxicity.
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Affiliation(s)
- Susie Youn
- Department of Surgery, University of Alberta, Edmonton, AB, Canada.
| | - Angela Chen
- Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Vincent Ha
- Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Carole Chambers
- Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Dean T Eurich
- School of Public Health, University of Alberta, Edmonton, AB, Canada
| | - Michael McCall
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Michael B Sawyer
- Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
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14
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Arshad U, Taubert M, Seeger-Nukpezah T, Ullah S, Spindeldreier KC, Jaehde U, Hallek M, Fuhr U, Vehreschild JJ, Jakob C. Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients. BMC Cancer 2021; 21:719. [PMID: 34147089 PMCID: PMC8214796 DOI: 10.1186/s12885-021-08443-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 06/02/2021] [Indexed: 12/03/2022] Open
Abstract
Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08443-x.
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Affiliation(s)
- Usman Arshad
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany. .,Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany.
| | - Max Taubert
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany
| | - Tamina Seeger-Nukpezah
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Sami Ullah
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany.,Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany
| | | | - Ulrich Jaehde
- Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany
| | - Michael Hallek
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Uwe Fuhr
- Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Str 24, 50931, Cologne, Germany
| | - Jörg Janne Vehreschild
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany.,Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine and University Hospital of Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Carolin Jakob
- Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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15
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Maddalena C, Ponsiglione A, Camera L, Santarpia L, Pasanisi F, Bruzzese D, Panico C, Fiore G, Camardella S, Caramia T, Farinaro A, De Placido S, Carlomagno C. Prognostic role of sarcopenia in metastatic colorectal cancer patients during first-line chemotherapy: A retrospective study. World J Clin Oncol 2021; 12:355-366. [PMID: 34131567 PMCID: PMC8173330 DOI: 10.5306/wjco.v12.i5.355] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 01/31/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sarcopenia is a condition characterized by decreased skeletal muscle mass due to physiological ageing or to a concomitant disease such as neoplasia. In cancer patients, a low lean body mass is suggested to be a negative prognostic factor for survival and for the development of dose-limiting chemotherapy toxicities irrespective of disease stage.
AIM To evaluate the prognostic role of sarcopenia in patients with metastatic colorectal cancer (mCRC) undergoing first-line chemotherapy.
METHODS Our retrospective analysis included 56 mCRC patients who received first-line chemotherapy from 2014 to 2017 at the Medical Oncology Unit of our hospital. Computerized scans were performed before starting chemotherapy and at the first disease reassessment. Sarcopenia was assessed using the skeletal mass index = muscle area in cm2/(height in m2) calculated at the L3 vertebra. Overall survival and objective response rate were evaluated. Toxicities were analyzed during the first four cycles of therapy and graded according to Common Terminology Criteria for Adverse Events version 4.0. A loss of skeletal muscle mass ≥ 5% was considered indicative of deterioration in muscle condition.
RESULTS Median age was 67 years and 35.7% of patients were ≥ 70 years old. Fourteen patients (25%) were sarcopenic at baseline computed tomography (CT) scan (7/33 men; 7/23 women); 5/14 sarcopenic patients were ≥ 70 years old. Median follow-up was 26.8 mo (3.8-66.8 mo) and median overall survival was 27.2 mo (95%CI: 23.3-37.3). Sarcopenia was not correlated to overall survival (P = 0.362), to higher toxicities reported during the first 4 cycles of chemotherapy (P = 1.0) or to response to treatment (P = 0.221). At the first disease reassessment, a skeletal muscle loss (SML) ≥ 5% was found in 17 patients (30.3%) 3 of whom were already sarcopenic at baseline CT scan, while 7 patients became sarcopenic. SML was not correlated to overall survival (P = 0.961). No statistically significant correlation was found between baseline sarcopenia and age (P = 1.0), body mass index (P = 0.728), stage at diagnosis (P = 0.355) or neutrophil/lymphocyte ratio (P = 0.751).
CONCLUSION Neither baseline sarcopenia nor SML affected survival. In addition, baseline sarcopenia was not related to worse treatment toxicity. However, these results must be interpreted with caution due to the limited sample size.
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Affiliation(s)
- Chiara Maddalena
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Andrea Ponsiglione
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Luigi Camera
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Lidia Santarpia
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Fabrizio Pasanisi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Dario Bruzzese
- Department of Public Health, University of Naples Federico II, Naples 80131, Italy
| | - Camilla Panico
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Giovanni Fiore
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Simona Camardella
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Tolomeo Caramia
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Alessia Farinaro
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Sabino De Placido
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Chiara Carlomagno
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
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Repellin CE, Ssemadaali MA, Newmyer S, Radhakrishnan H, Javitz HS, Bhatnagar P. NK-Cell Biofactory as an Off-the-Shelf Cell-based Vector for Targeted In Situ Synthesis of Engineered Proteins. Adv Biol (Weinh) 2021; 5:e2000298. [PMID: 33871182 DOI: 10.1002/adbi.202000298] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 02/27/2021] [Indexed: 11/07/2022]
Abstract
The NK-92MI, a fast-growing cytolytic cell line with a track record of exerting clinical efficacy, is transformed into a vector for synthesizing calibrated amounts of desired engineered proteins at our disease site, that is, NK-cell Biofactory. This provides an allogeneic option to the previously published T-cell-based living vector that is limited by high manufacturing cost and product variability. The modularity of this pathway, which combines a "target" receptor with an "effector" function, enables reprogramming of the NK-cell Biofactory to target diseases with specific molecular biomarkers, such as cancer, viral infections, or auto-immune disorders, and overcome barriers that may affect the advancement of NK-cell therapies.
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Affiliation(s)
| | | | - Sherri Newmyer
- Biosciences Division SRI International, Menlo Park, CA, 94025, USA
| | | | - Harold S Javitz
- Education Division, SRI International, Menlo Park, CA, 94025, USA
| | - Parijat Bhatnagar
- Biosciences Division SRI International, Menlo Park, CA, 94025, USA
- Cancer Imaging and Early Detection Program, Stanford Cancer Institute, Stanford, CA, 94305, USA
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17
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Chatelut E, Hendrikx JJMA, Martin J, Ciccolini J, Moes DJAR. Unraveling the complexity of therapeutic drug monitoring for monoclonal antibody therapies to individualize dose in oncology. Pharmacol Res Perspect 2021; 9:e00757. [PMID: 33745217 PMCID: PMC7981594 DOI: 10.1002/prp2.757] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022] Open
Abstract
Monoclonal antibodies (Mabs) have become key drugs in cancer treatment, either as targeted therapies or more recently as immune checkpoint inhibitors (ICIs). The fact that only some patients benefit from these drugs poses the usual question in the field of onco-hematology: that of the benefit of individual dosing and the potential of therapeutic drug monitoring (TDM) to carry out this individualization. However, Mabs present unique pharmacological characteristics for TDM, and the pharmacokinetic-pharmacodynamic relationship observed should be interpreted differently than that observed for conventional drugs and small molecules. This pharmacology practice review has been summarized from a public debate between the authors at the International TDM and Clinical Toxicology meeting in Banff, 2020, regarding the potential roles of TDM in the Mab/ICI setting.
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Affiliation(s)
- Etienne Chatelut
- CRCTUniversité de ToulouseInserm, and Institut Claudius‐RegaudIUCT‐OncopoleToulouseFrance
| | - Jeroen J. M. A. Hendrikx
- Department of Pharmacy and Pharmacology and Department of Nuclear MedicineThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Jennifer Martin
- Centre for Drug Repurposing and Medicines ResearchThe University of NewcastleCallaghanNSWAustralia
| | - Joseph Ciccolini
- SMARTcCRCM Inserm U1068Aix Marseille University and La Timone university Hospital of MarseilleMarseilleFrance
| | - Dirk Jan A. R. Moes
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
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18
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Sheng J, Zhang J, Baudelet C, Roy A. Clinical Benefit-Risk Assessment of Nivolumab 240 mg Every 2 Weeks in Chinese Patients With Advanced and Metastatic Solid Tumors. J Clin Pharmacol 2021; 61:1045-1053. [PMID: 33501654 PMCID: PMC8359491 DOI: 10.1002/jcph.1821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/21/2021] [Indexed: 12/11/2022]
Abstract
Nivolumab 240 mg every 2 weeks is approved in China by the National Medical Product Agency for squamous cell carcinoma of the head and neck and gastric cancer, based on population pharmacokinetic (PPK) analyses and benefit-risk assessment of safety/efficacy in solid tumors, including Chinese and global populations. The aim of this assessment was to investigate exposure and risk for adverse events (AEs) with flat dosing compared with weight-based dosing. Nivolumab 240-mg and 3-mg/kg every-2-week exposures in Chinese patients were simulated using PPK modeling, and AEs in Chinese and pooled global populations were compared by dosing regimen, exposure, and weight. The 10-mg/kg every-2-week regimen was included because it is known to be well tolerated. Predicted nivolumab exposure in Chinese patients receiving 240 mg every 2 weeks was ∼25% higher versus 3 mg/kg every 2 weeks, but ∼60% lower versus 10 mg/kg every 2 weeks. Grade 3/4 AE incidence in Chinese patients receiving nivolumab 3 mg/kg every 2 weeks was similar with 240-mg every-2-week dosing and with patients from global populations treated with 3 or 10 mg/kg every 2 weeks. There was no trend toward increased AE incidence with high versus low nivolumab exposure or in global patients of varying body weight receiving 3 or 10 mg/kg every 2 weeks. Objective response rates were similar in Chinese and global patients with squamous and nonsquamous NSCLC. Results showed that benefit-risk profiles with nivolumab 240 mg every 2 weeks were similar to those of the 3-mg/kg every-2-week regimen in Chinese patients and global populations, providing an alternative treatment option to Chinese patients.
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Affiliation(s)
| | - Jason Zhang
- Bristol Myers Squibb, Lawrenceville, New Jersey, USA
| | | | - Amit Roy
- Bristol Myers Squibb, Lawrenceville, New Jersey, USA
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19
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Jin KT, Chen B, Liu YY, Lan HUR, Yan JP. Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in the treatment of colorectal cancer. Cancer Cell Int 2021; 21:83. [PMID: 33522929 PMCID: PMC7851946 DOI: 10.1186/s12935-021-01763-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. The immunotherapy approaches try to elicit patients` immune responses against tumor cells to eradicate the tumor. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. MAbs demonstrate the great ability to completely recognize cancer cell-surface receptors and blockade proliferative or inhibitory pathways. On the other hand, T cell activation by genetically engineered CAR receptor via the TCR/CD3 and costimulatory domains can induce potent immune responses against specific tumor-associated antigens (TAAs). Both of these approaches have beneficial anti-tumor effects on CRC. Herein, we review the different mAbs against various pathways and their applications in clinical trials, the different types of CAR-T cells, various specific CAR-T cells against TAAs, and their clinical use in CRC treatment.
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Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hosptial, Zhejiang University School of Medicine, Zhejiang Province, Jinhua, 312000, P.R. China
| | - Bo Chen
- Department of Neurology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China
| | - Yu-Yao Liu
- Department of Colorectal Surgery, Affiliated Jinhua Hosptial, Zhejiang University School of Medicine, Zhejiang Province, Jinhua, 312000, P.R. China
| | - H Uan-Rong Lan
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hosptial, Zhejiang University School of Medicine, Zhejiang Province, Jinhua, 312000, P.R. China
| | - Jie-Ping Yan
- Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, China.
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20
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Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer. Mol Imaging Biol 2021; 22:156-164. [PMID: 31054001 DOI: 10.1007/s11307-019-01358-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PURPOSE To identify the optimal dosing strategy for fluorescence-guided surgery in patients with head and neck squamous cell carcinoma, we conducted a dose-ranging study evaluating the anti-epidermal growth factor receptor (EGFR) therapeutic antibody, panitumumab, that was fluorescently labeled with the near-infrared dye IRDye800CW. PROCEDURES Patients (n = 24) received either 0.5 or 1.0 mg/kg panitumumab-IRDye800CW in the weight-based dosing group or 25 or 50 mg panitumumab-IRDye800CW in the fixed dosing group. Following surgery, whole primary specimens were imaged in a closed-field device and the mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were assessed. Clinical variables, including dose, time of infusion-to-surgery, age, unlabeled dose, gender, primary tumor site, and tumor size, were analyzed to evaluate the factors affecting the fluorescence intensity in order to identify the optimal dose for intraoperative fluorescence imaging. RESULTS A total of 24 primary tumor specimens were imaged and analyzed in this study. Although no correlations between TBR and dose of panitumumab-IRDye800CW were found, there were moderate-strong correlations between the primary tumor MFI and panitumumab-IRDye800CW dose for fixed dose (mg) (R2 = 0.42) and for dose/weight (mg/kg) (R2 = 0.54). Results indicated that the optimal MFI was at approximately 50 mg for fixed dose and 0.75 mg/kg for dose/weight. No significant differences were found for the primary tumor MFI and TBRs between the weight-based dosing and the fixed dosing groups. MFIs significantly increased when the infusion-to-surgery window was reduced to within 2 days (vs. 3 days or more, p < 0.05). CONCLUSIONS Antibody-based imaging for surgical resection is under investigation in multiple clinical trials. Our data suggests that a fixed dose of 50 mg is an appropriate diagnostic dose for successful surgical fluorescence imaging.
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21
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Genkel V, Kuznetcova A, Shaposhnik I. Relationship between the abdominal aortic diameter and carotid atherosclerosis in middle-aged patients without established atherosclerotic cardiovascular diseases. INT ANGIOL 2021; 40:131-137. [PMID: 33463974 DOI: 10.23736/s0392-9590.21.04493-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The purpose of our research was to study the relationship between the diameter of abdominal aorta (AA) and subclinical atherosclerosis in patients without established atherosclerotic cardiovascular diseases (ASCD) in the absence of pathological enlargement of AA. METHODS The study included 136 patients (52.9% male, 47.1% female), median age was 51.0 (45.5; 58.0) years. The maximum diameter of AA was measured in the infrarenal region at a level between the place of origin of the lower renal artery and bifurcation in cross section. Measurement of the anteroposterior diameter of AA was carried out from the outer-to-outer edge (OTO). Also, we determined the Aortic Size Index (ASI) with respect to body surface area (BSA), using the values of BSA obtained by five different formulas validated for use in clinical practice. All patients underwent carotid duplex ultrasound scanning with assessment of degree of carotid stenosis (according to ECST criteria). RESULTS An increase in the anteroposterior diameter of AA was directly correlated with maximum stenosis of carotid arteries (r=0.186; P=0.030). According to the results of a logistic regression analysis an increase in the diameter of AA by 1 mm was associated with an increase in the relative risk of carotid stenosis ≥50% by 1.37 times (95% CI: 1.01-1.85; P=0.041) after adjustment. Thus, an increase in diameter of AA of more than 1.75 cm with a sensitivity of 71.4% and a specificity of 73.0% made it possible to predict the presence of stenosis of the carotid arteries ≥50%. An increase in ASI<inf>Boyd</inf> (BSA was calculated using Boyd's formula) of more than 0.84 allowed predicting the presence of stenosis of the carotid arteries ≥50% with a sensitivity of 85.7% and a specificity of 65.6%. CONCLUSIONS In middle-aged patients without established ASCD, the diameter of AA and ASI directly correlated with the degree of carotid stenosis (according to ECST criteria). The diameter of AA and ASI demonstrated good sensitivity and specificity for the presence of asymptomatic carotid stenosis of ≥50%.
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Affiliation(s)
- Vadim Genkel
- Department of Internal Medicine, South-Ural State Medical University, Chelyabinsk, Russia -
| | - Alla Kuznetcova
- Department of Hospital Therapy, South-Ural State Medical University, Chelyabinsk, Russia
| | - Igor Shaposhnik
- Department of Internal Medicine, South-Ural State Medical University, Chelyabinsk, Russia
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22
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Celik E, Samanci NS, Karadag M, Demirci NS, Demirelli FH, Ozguroglu M. The relationship between eGFR and capecitabine efficacy/toxicity in metastatic breast cancer. Med Oncol 2021; 38:11. [PMID: 33452614 DOI: 10.1007/s12032-021-01457-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/01/2021] [Indexed: 11/27/2022]
Abstract
The objective of this study was to evaluate the efficacy and toxicity of capecitabine in metastatic breast cancer (mBC) according to the estimated glomerular filtration rate (eGFR). A total of 135 patients included in the final analysis were stratified into 3 categories according to baseline eGFR, i.e., eGFR <60 mL/min/1.73 m2 (Group 1), eGFR 60-90 mL/min/1.73 m2 (Group 2) and eGFR >90 mL/min/1.73 m2 (Group 3). If a patient developed a level of toxicity that would lead to capecitabine dose reduction, this was recognized as dose-limiting toxicity (DLT). The dose was reduced due to toxicity in 95 cycles. A total of 95 DLTs were seen in 76 (56.2%) of the 135 patients. When 76 patients with DLT were evaluated according to eGFR, DLT was observed in 93.3% of those in Group 1, 72.5% of those in Group 2 and 41.3% of those in Group 3 (p < 0.001). The median time to progression (TTP) of all patients was 7.4 months. No significant difference in TTP was observed in patients stratified into 3 groups according to eGFR. When the patients were divided into two groups as DLT and without DLT, the median TTP was 8.68 months (95% CI, 7.53-9.81 months) in those with toxicity and 6.23 months (95% CI, 4.04-8.43 months) in those without toxicity (log-rank p = 0.004). We found a significant relationship between low eGFR and increased risk of DLT. Having a DLT was associated with a longer TTP. It indicates the need for more data/larger study investigating these discrepancies.
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Affiliation(s)
- Emir Celik
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey.
| | - Nilay Sengul Samanci
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
| | - Mehmet Karadag
- Faculty of Medicine, Department of Biostatistics, Hatay Mustafa Kemal University, Antakya, Turkey
| | - Nebi Serkan Demirci
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
| | - Fuat Hulusi Demirelli
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
| | - Mustafa Ozguroglu
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
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van Doorn L, Crombag MRBS, Rier HN, van Vugt JLA, van Kesteren C, Bins S, Mathijssen RHJ, Levin MD, Koolen SLW. The Influence of Body Composition on the Systemic Exposure of Paclitaxel in Esophageal Cancer Patients. Pharmaceuticals (Basel) 2021; 14:ph14010047. [PMID: 33435449 PMCID: PMC7827486 DOI: 10.3390/ph14010047] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/10/2020] [Accepted: 01/07/2021] [Indexed: 12/30/2022] Open
Abstract
Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with esophageal cancer. Skeletal muscle index (SMI), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were measured at the third lumbar vertebra on computed tomography (CT) scans performed before treatment. Paclitaxel PK data were collected from a prospective study performed between May 2004 and January 2014. Non-linear mixed-effects modeling was used to fit paclitaxel PK profiles and evaluate the covariates body surface area (BSA), SMI, VAT, and SMD using a significance threshold of p < 0.001. Paclitaxel was administered to 184 patients in a dose range of 50 to 175 mg/m2. Median BSA was 1.98 m2 (range of 1.4 to 2.8 m2). SMI, VAT, and SMD were not superior to BSA in predicting paclitaxel PK. The additive value of SMI, VAT, and SMD to BSA was also negligible. We did not find evidence that paclitaxel dosing could be further optimized by correcting for SMI, VAT, or SMD.
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Affiliation(s)
- Leni van Doorn
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (S.B.); (R.H.J.M.); (S.L.W.K.)
- Correspondence:
| | - Marie-Rose B. S. Crombag
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands;
| | - Hánah N. Rier
- Department of Internal Medicine, Albert Schweitzer Hospital, 3318 AT Dordrecht, The Netherlands; (H.N.R.); (M.-D.L.)
| | - Jeroen L. A. van Vugt
- Department of Surgery, Erasmus MC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands;
| | | | - Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (S.B.); (R.H.J.M.); (S.L.W.K.)
| | - Ron H. J. Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (S.B.); (R.H.J.M.); (S.L.W.K.)
| | - Mark-David Levin
- Department of Internal Medicine, Albert Schweitzer Hospital, 3318 AT Dordrecht, The Netherlands; (H.N.R.); (M.-D.L.)
| | - Stijn L. W. Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (S.B.); (R.H.J.M.); (S.L.W.K.)
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands;
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Dong W, Chen M, Wang J, Xia L, Wang Q, Nie X, Feng Y, Fang Y. rHuPH20-facilitated subcutaneous administration of monoclonal antibodies in cancer therapy. Immunotherapy 2020; 13:79-88. [PMID: 33198539 DOI: 10.2217/imt-2020-0204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim: This meta-analysis aimed to evaluate the pharmacokinetics, efficacy, safety and immunogenicity of rHuPH20-facilitated subcutaneous (SC) administration of monoclonal antibody compared with intravenous (IV) administration for patients with cancer. Materials & methods: Outcomes included trough concentrations (Ctrough), overall response rate, adverse events, serious adverse events and antidrug antibody positivity rate. Subgroup analysis was also performed. Results: Five studies involving 1575 participants (788/787) were included. All studies met the non-inferiority criterion in Ctrough. No significant differences were observed in overall response rate (p = 0.12), adverse events (p = 0.05), and severe adverse events (p = 0.73) between SC and IV groups. The SC group also had lower immunogenicity than the IV group. Conclusion: rHuPH20-facilitated subcutaneous administration of monoclonal antibody is highly similar to IV administration in terms of pharmacokinetics, efficacy, and safety, but with lower immunogenicity.
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Affiliation(s)
- Wenliang Dong
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, China
| | - Min Chen
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, China
| | - Jiaxue Wang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China.,Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, China
| | - Lin Xia
- School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Qian Wang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Xiaoyan Nie
- Department of Pharmacy Administration & Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, China
| | - Yufei Feng
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Yi Fang
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
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Electrochemical biosensors: a nexus for precision medicine. Drug Discov Today 2020; 26:69-79. [PMID: 33137482 DOI: 10.1016/j.drudis.2020.10.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/18/2020] [Accepted: 10/23/2020] [Indexed: 12/29/2022]
Abstract
Precision medicine is a field with huge potential for improving a patient's quality of life, wherein therapeutic drug monitoring (TDM) can provide actionable insights. More importantly, incorrect drug dose is a common contributor to medical errors. However, current TDM practice is time-consuming and expensive, and requires specialised technicians. One solution is to use electrochemical biosensors (ECBs), which are inexpensive, portable, and highly sensitive. In this review, we explore the potential for ECBs as a technology for on-demand drug monitoring, including microneedles, continuous monitoring, synthetic biorecognition elements, and multi-material electrodes. We also highlight emerging strategies to achieve continuous drug monitoring, and conclude by appraising recent developments and providing an outlook for the field.
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26
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Le Louedec F, Leenhardt F, Marin C, Chatelut É, Evrard A, Ciccolini J. Cancer Immunotherapy Dosing: A Pharmacokinetic/Pharmacodynamic Perspective. Vaccines (Basel) 2020; 8:E632. [PMID: 33142728 PMCID: PMC7712135 DOI: 10.3390/vaccines8040632] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/12/2020] [Accepted: 10/15/2020] [Indexed: 12/11/2022] Open
Abstract
Immune check-point inhibitors are drugs that are markedly different from other anticancer drugs because of their indirect mechanisms of antitumoral action and their apparently random effect in terms of efficacy and toxicity. This marked pharmacodynamics variability in patients calls for reconsidering to what extent approved dosing used in clinical practice are optimal or whether they should require efforts for customization in outlier patients. To better understand whether or not dosing could be an actionable item in oncology, in this review, preclinical and clinical development of immune checkpoint inhibitors are described, particularly from the angle of dose finding studies. Other issues in connection with dosing issues are developed, such as the flat dosing alternative, the putative role therapeutic drug monitoring could play, the rise of combinatorial strategies, and pharmaco-economic aspects.
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Affiliation(s)
- Félicien Le Louedec
- Institut Claudius-Regaud, Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, and Cancer Research Center of Toulouse (CRCT), Inserm U1037, University of Toulouse, 31100 Toulouse, France;
| | - Fanny Leenhardt
- Institut de Cancérologie de Montpellier (ICM) and Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, University of Montpellier, 34090 Montpellier, France;
| | - Clémence Marin
- Assistance Publique—Hôpitaux de Marseille (AP-HM) and Simulation Modeling Adaptive Response for Therapeutics in cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, Aix Marseille University, 13009 Marseille, France; (C.M.); (J.C.)
| | - Étienne Chatelut
- Institut Claudius-Regaud, Institut Universitaire du Cancer de Toulouse (IUCT)-Oncopole, and Cancer Research Center of Toulouse (CRCT), Inserm U1037, University of Toulouse, 31100 Toulouse, France;
| | - Alexandre Evrard
- Centre Hospitalier Universitaire de Nîmes Carémeau, Nîmes, France and IRCM U1194, University of Montpellier, 34090 Montpellier, France;
| | - Joseph Ciccolini
- Assistance Publique—Hôpitaux de Marseille (AP-HM) and Simulation Modeling Adaptive Response for Therapeutics in cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, Aix Marseille University, 13009 Marseille, France; (C.M.); (J.C.)
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27
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Gupta N, Wang X, Offman E, Prohn M, Narasimhan N, Kerstein D, Hanley MJ, Venkatakrishnan K. Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer. Clin Pharmacokinet 2020; 60:235-247. [PMID: 32816246 PMCID: PMC7862202 DOI: 10.1007/s40262-020-00929-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Background and objectives Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. Methods Plasma concentration–time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). Results Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. Conclusions Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib. Electronic supplementary material The online version of this article (10.1007/s40262-020-00929-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Neeraj Gupta
- Quantitative Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.
| | | | | | | | - Narayana Narasimhan
- ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.,Verastem Oncology, Needham, MA, USA
| | - David Kerstein
- ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.,Anchiano Therapeutics, Cambridge, MA, USA
| | - Michael J Hanley
- Quantitative Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA
| | - Karthik Venkatakrishnan
- Quantitative Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.,EMD Serono Research and Development Institute, Billerica, MA, USA
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28
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Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, Casasnovas O, Hamad N, Zijlstra JM, Bakhshi S, Bouabdallah R, Choquet S, Gurion R, Hill B, Jaeger U, Sancho JM, Schuster M, Thieblemont C, De la Cruz F, Egyed M, Mishra S, Offner F, Vassilakopoulos TP, Warzocha K, McCarthy D, Ma X, Corona K, Saint-Martin JR, Chang H, Landesman Y, Joshi A, Wang H, Shah J, Shacham S, Kauffman M, Van Den Neste E, Canales MA. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol 2020; 7:e511-e522. [PMID: 32589977 DOI: 10.1016/s2352-3026(20)30120-4] [Citation(s) in RCA: 198] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/10/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING Karyopharm Therapeutics Inc.
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Affiliation(s)
| | | | - Federica Cavallo
- Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Turin, Italy
| | | | - Andre Goy
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | | | | | - Nada Hamad
- St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia
| | - Josée M Zijlstra
- Amsterdam UMC, Vrije Universiteit, Cancer Center, Amsterdam, Netherlands
| | - Sameer Bakhshi
- Dr B R Ambedkar Institute Rotary Cancer Hospital AIIMS, New Delhi, India
| | | | | | - Ronit Gurion
- Rabin Medical Centre, Petah Tiqwa, Israel; Tel Aviv University, Petah Tiqwa, Israel
| | | | | | | | | | | | | | | | - Sourav Mishra
- Institute of Medical Sciences & SUM Hospital, Odisha, India
| | | | | | | | | | - Xiwen Ma
- Karyopharm Therapeutics Inc, Newton, MA, USA
| | | | | | - Hua Chang
- Karyopharm Therapeutics Inc, Newton, MA, USA
| | | | - Anita Joshi
- Karyopharm Therapeutics Inc, Newton, MA, USA
| | | | - Jatin Shah
- Karyopharm Therapeutics Inc, Newton, MA, USA
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29
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Krens SD, Lassche G, Jansman FGA, Desar IME, Lankheet NAG, Burger DM, van Herpen CML, van Erp NP. Dose recommendations for anticancer drugs in patients with renal or hepatic impairment. Lancet Oncol 2020; 20:e200-e207. [PMID: 30942181 DOI: 10.1016/s1470-2045(19)30145-7] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 02/19/2019] [Accepted: 02/19/2019] [Indexed: 01/22/2023]
Abstract
Renal or hepatic impairment is a common comorbidity for patients with cancer either because of the disease itself, toxicity of previous anticancer treatments, or because of other factors affecting organ function, such as increased age. Because renal and hepatic function are among the main determinants of drug exposure, the pharmacokinetic profile might be altered for patients with cancer who have renal or hepatic impairment, necessitating dose adjustments. Most anticancer drugs are dosed near their maximum tolerated dose and are characterised by a narrow therapeutic index. Consequently, selecting an adequate dose for patients who have either hepatic or renal impairment, or both, is challenging and definitive recommendations on dose adjustments are scarce. In this Review, we discuss the effect of renal and hepatic impairment on the pharmacokinetics of anticancer drugs. To guide clinicians in selecting appropriate dose adjustments, information from available drug labels and from the published literature were combined to provide a practical set of recommendations for dose adjustments of 160 anticancer drugs for patients with hepatic and renal impairment.
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Affiliation(s)
- Stefanie D Krens
- Department of Clinical Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands
| | - Gerben Lassche
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Frank G A Jansman
- Department of Pharmacy, Deventer Hospital, Deventer, Netherlands; PharmacoTherapy, Epidemiology and Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands
| | - Ingrid M E Desar
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Nienke A G Lankheet
- Department of Clinical Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands; Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede, Netherlands
| | - David M Burger
- Department of Clinical Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands
| | - Carla M L van Herpen
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Nielka P van Erp
- Department of Clinical Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands.
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Menz BD, Stocker SL, Verougstraete N, Kocic D, Galettis P, Stove CP, Reuter SE. Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology. Br J Clin Pharmacol 2020; 87:227-236. [PMID: 32430968 DOI: 10.1111/bcp.14372] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 12/12/2022] Open
Abstract
There are few fields of medicine in which the individualisation of medicines is more important than in the area of oncology. Under-dosing can have significant ramifications due to the potential for therapeutic failure and cancer progression; by contrast, over-dosing may lead to severe treatment-limiting side effects, such as agranulocytosis and neutropenia. Both circumstances lead to poor patient prognosis and contribute to the high mortality rates still seen in oncology. The concept of dose individualisation tailors dosing for each individual patient to ensure optimal drug exposure and best clinical outcomes. While the value of this strategy is well recognised, it has seen little translation to clinical application. However, it is important to recognise that the clinical setting of oncology is unlike that for which therapeutic drug monitoring (TDM) is currently the cornerstone of therapy (e.g. antimicrobials). Whilst there is much to learn from these established TDM settings, the challenges presented in the treatment of cancer must be considered to ensure the implementation of TDM in clinical practice. Recent advancements in a range of scientific disciplines have the capacity to address the current system limitations and significantly enhance the use of anticancer medicines to improve patient health. This review examines opportunities presented by these innovative scientific methodologies, specifically sampling strategies, bioanalytics and dosing decision support, to enable optimal practice and facilitate the clinical implementation of TDM in oncology.
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Affiliation(s)
- Bradley D Menz
- SA Pharmacy, Flinders Medical Centre, Adelaide, SA, Australia
| | - Sophie L Stocker
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, NSW, Australia.,St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Nick Verougstraete
- Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.,Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Danijela Kocic
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, NSW, Australia.,St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Peter Galettis
- Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Christophe P Stove
- Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Stephanie E Reuter
- UniSA Clinical & Health Sciences, University of South Australia, Adelaide, SA, Australia
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Matheron A, Guerault MN, Vazquez R, Cheron M, Brossard D, Crauste-Manciet S. Microbiological stability tests with simulated broth preparations and integrity testing for sterile standard cytotoxic preparations. PHARMACEUTICAL TECHNOLOGY IN HOSPITAL PHARMACY 2020. [DOI: 10.1515/pthp-2020-0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AbstractObjectivesThe objectives were to assess the microbiological stability and the physical enclosure integrity of the overwrapping for batch production of standard cytotoxic injectable solutions.MethodsBroth culture media were used in place of cytotoxic drugs to assess the worst case in term of microbiological contamination risk. Iterative sterility tests on batches were performed for 60 days using rapid microbiological method. Validation of microbiological growth of culture media was assessed by direct inoculation of <100 CFU/mL of six microbiological strains recommended by European Pharmacopeia. Validation of the ability of growth of microorganisms in 11 cytotoxic solutions and one monoclonal antibody was assessed using eight strains. In addition, the physical integrity of the seal of the overwrapping containing cytotoxic preparations was assessed by dynamometric method and dye penetration test.ResultsNo microbiological contamination was observed on all units of batches for 60 days of investigation. The ability to detect microbiological growth in cytotoxic solutions was validated for the eight challenge microorganisms after 1/10 dilution for cytotoxic investigated, except for 5 Fluorouracil, gemcitabine and cisplatin. In addition, physical integrity testing of the seal of overwrapping pointed out the need of specific validation of heatsealer and operator education.ConclusionsBesides physico-chemical testing, microbiological stability testing combined to physical integrity testing is the additional part of the development method for batch production of sterile drugs in hospital.
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Affiliation(s)
- Agnès Matheron
- CHI Poissy Saint Germain-en-Laye, Saint Germain-en-Laye, France
| | | | - Raphael Vazquez
- CHI Poissy Saint Germain-en-Laye, Saint Germain-en-Laye, France
| | - Mireille Cheron
- CHI Poissy Saint Germain-en-Laye, Saint Germain-en-Laye, France
| | - Denis Brossard
- CHI Poissy Saint Germain-en-Laye, Saint Germain-en-Laye, France
- Paris Descartes University, Faculty of Pharmacy, Paris, France
| | - Sylvie Crauste-Manciet
- University of Bordeaux, ARNA Laboratory U1212 INSERM, UMR 5320 CNRS, Bordeaux, France
- University Hospital of Bordeaux (CHU), Bordeaux, France
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Radhakrishnan H, Javitz HS, Bhatnagar P. Lentivirus Manufacturing Process for Primary T-Cell Biofactory Production. ACTA ACUST UNITED AC 2020; 4:e1900288. [PMID: 32390316 DOI: 10.1002/adbi.201900288] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/08/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023]
Abstract
A process for maximizing the titer of lentivirus particles, deemed to be a necessity for transducing primary cells, is developed. Lentivirus particles, with a set of transgenes encoding an artificial cell-signaling pathway, are used to transform primary T cells as vectors for calibrated synthesis of desired proteins in situ, that is, T-cell biofactory cells. The process is also used to generate primary T cells expressing antigen-specific chimeric antigen receptors, that is, CAR T cells. The two differently engineered primary T cells are expanded and validated for their respective functions, that is, calibrated synthesis of desired proteins upon engaging the target cells, which is specific for the T-cell biofactory cells, and cytolysis of the target cells common to both types of cells. The process is compliant with current Good Manufacturing Practices and can be used to support the scale-up for clinical translation.
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Affiliation(s)
| | - Harold S Javitz
- Education Division, SRI International, Menlo Park, CA, 94025, USA
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Therapeutic Drug Monitoring of Oral Anticancer Drugs: The Dutch Pharmacology Oncology Group-Therapeutic Drug Monitoring Protocol for a Prospective Study. Ther Drug Monit 2020; 41:561-567. [PMID: 31568233 DOI: 10.1097/ftd.0000000000000654] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes. METHODS In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase. DISCUSSION Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.
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Hu X, Wildman KP, Basu S, Lin PL, Rowntree C, Saha V. The cost-effectiveness of pegaspargase versus native asparaginase for first-line treatment of acute lymphoblastic leukaemia: a UK-based cost-utility analysis. HEALTH ECONOMICS REVIEW 2019; 9:40. [PMID: 31885053 PMCID: PMC6935472 DOI: 10.1186/s13561-019-0257-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 12/10/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND L-asparaginase is a key component of treatment for patients with acute lymphoblastic leukaemia (ALL) in the UK. Commonly used forms of asparaginase are native E. coli-derived asparaginase (native asparaginase) and pegaspargase in first-line combination therapy, and native Erwinia chrysanthemi-derived asparaginase (Erwinia asparaginase) as second-line treatment. The objective of this study was to evaluate the cost-effectiveness of pegaspargase versus native asparaginase in first-line combination therapy for patients with newly diagnosed ALL. A combined decision tree and health-state transition Markov cost-effectiveness model was developed to assess the relative costs and health outcomes of pegaspargase versus native asparaginase in the UK setting. RESULTS In base case analyses, first-line pegaspargase (followed by Erwinia asparaginase in cases of hypersensitivity) dominated first-line native asparaginase followed by Erwinia asparaginase; i.e. resulted in lower costs and more quality-adjusted life year gain. The favourable hypersensitivity rates and administration profile of pegaspargase led to lifetime cost savings of £4741 versus native asparaginase. Pegaspargase remained cost-effective versus all treatment strategies in all scenario analyses, including use of the 2500 IU/m2 dose, recommended for patients ≤21 years of age. CONCLUSIONS Pegaspargase, as part of multi-drug chemotherapy, is a cost-effective option for the treatment of newly diagnosed ALL. Based on this study, The National Institute for Health and Care Excellence Technology Appraisal Committee concluded that it could recommend pegaspargase as a cost-effective use of National Health Service resources in England & Wales for treating ALL in children, young people and adults with untreated, newly diagnosed disease. TRIAL REGISTRATION UKALL 2011, EudraCT number 2010-020924-22; UKALL 2003, EudraCT number 2007-004013-34; UKALL14, EudraCT number 2009-012717-22.
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Affiliation(s)
- Xingdi Hu
- GHEOR Analytics, Shire, Cambridge, MA USA
| | - Kingsley P. Wildman
- Medical Affairs for Oncology, UK & Ireland, Servier Laboratories Ltd, Stoke Poges, UK
| | - Subham Basu
- Medical Affairs Oncology, UK & Republic of Ireland, Shire Pharmaceuticals Ltd, London, UK
| | | | | | - Vaskar Saha
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, The Oglesby Cancer Research Building, 555 Wilmslow Road, Manchester, M20 4GJ UK
- Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India
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de Sena LWP, Mello AGNC, Ferreira MVD, de Ataide MA, Dias RM, Vieira JLF. Doses of chloroquine in the treatment of malaria by Plasmodium vivax in patients between 2 and 14 years of age from the Brazilian Amazon basin. Malar J 2019; 18:439. [PMID: 31864358 PMCID: PMC6925880 DOI: 10.1186/s12936-019-3072-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 12/13/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND A total dose of chloroquine of 25 mg/kg is recommended by the World Health Organization (WHO) to treat malaria by Plasmodium vivax. In several endemic areas, including the Brazilian Amazon basin, anti-malarial drugs are dispensed in small plastic bags at a dosing regimen based on age. This practice can lead to suboptimal dosing of the drug, which can impact treatment outcomes. The aim of the present study was to estimate the extent of sub-dosing of chloroquine in children and adolescents with vivax malaria using an age-based dose regimen, in addition to investigating the influence of age on the plasma concentrations of chloroquine and desethylchloroquine. METHODS A study of cases was conducted with male patients with a confirmed infection by P. vivax, ages 2 to 14 years, using a combined regimen of chloroquine and primaquine. Height, weight and body surface area were determined at admission on the study. The total dose of chloroquine administered was estimated based on the weight and on the body surface area of the study patients. Chloroquine and desethylchloroquine were measured on Day 7 in each patient included in the study by a high-performance liquid chromatographic method with fluorescence detection. RESULTS A total of 81 patients were enrolled and completed the study. The median age was 9 years (2-14 years). All patients presented negative blood smears at 42 days follow-up. The total dose of chloroquine ranged from 13.1 to 38.1 mg/kg. The percentage of patients with a total dose of the drug below 25 mg/kg ranged from 29.4 to 63.6%. The total dose of chloroquine administered based on BSA ranged from 387 to 1079 mg/m2, increasing with age. Plasma chloroquine concentrations ranged from 107 to 420 ng/ml, increasing with age. For desethylchloroquine, the plasma concentrations ranged from 167 to 390 ng/ml, with similar values among age-groups. CONCLUSION The data demonstrated the widespread exposure of children and adolescents to suboptimal doses of chloroquine in the endemic area investigated.
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Affiliation(s)
- Luann Wendel Pereira de Sena
- Pharmacy Faculty, Para Federal University, Campus Universitario do Guama, Augusto Correa Street 01, Belem, Para, 66074740, Brazil
| | | | - Michelle Valéria Dias Ferreira
- Pharmacy Faculty, Para Federal University, Campus Universitario do Guama, Augusto Correa Street 01, Belem, Para, 66074740, Brazil
| | - Marcieni Andrade de Ataide
- Pharmacy Faculty, Para Federal University, Campus Universitario do Guama, Augusto Correa Street 01, Belem, Para, 66074740, Brazil
| | - Rosa Maria Dias
- Pharmacy Faculty, Para Federal University, Campus Universitario do Guama, Augusto Correa Street 01, Belem, Para, 66074740, Brazil
| | - José Luiz Fernandes Vieira
- Pharmacy Faculty, Para Federal University, Campus Universitario do Guama, Augusto Correa Street 01, Belem, Para, 66074740, Brazil.
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Visser S, Koolen SLW, de Bruijn P, Belderbos HNA, Cornelissen R, Mathijssen RHJ, Stricker BH, Aerts JGJV. Pemetrexed exposure predicts toxicity in advanced non-small-cell lung cancer: A prospective cohort study. Eur J Cancer 2019; 121:64-73. [PMID: 31561135 DOI: 10.1016/j.ejca.2019.08.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/21/2019] [Accepted: 08/05/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND We explored whether total exposure to pemetrexed predicts effectiveness and toxicity in advanced non-small-cell lung cancer (NSCLC). Furthermore, we investigated alternative dosing schedules. METHODS In this prospective cohort study, patients with advanced NSCLC receiving first- or second-line pemetrexed(/platinum) were enrolled. Plasma sampling was performed weekly (cyclePK) and within 24 h (24hPK) after pemetrexed administration. With population pharmacokinetic/pharmacodynamic modelling, total exposure to pemetrexed during cycle 1 (area under the curve during chemotherapy cycle 1 [AUC1]) was estimated and related to progression-free survival (PFS)/overall survival (OS). We compared mean AUC1 (mg·h/L) in patients with and without severe chemotherapy-related adverse events (AEs) during total treatment. Second, different dosing schedules were simulated to minimise the estimated variability (coefficient of variation [CV]) of AUC. RESULTS For 106 of 165 patients, concentrations of pemetrexed were quantified (24hPK, n = 15; cyclePK, n = 106). After adjusting for prognostic factors, sex, disease stage and World Health Organisation performance score, AUC1 did not predict PFS/OS in treatment-naive patients (n = 95) (OS, hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.00-1.11; PFS, HR = 1.03, 95% CI: 0.98-1.08). Patients with severe chemotherapy-related AEs (n = 55) had significantly higher AUC1 values than patients without them (n = 51) (226 ± 53 vs 190 ± 31, p < 0.001). Compared with body surface area-based dosing (CV: 22.5%), simulation of estimated glomerular filtration rate (eGFR)-based dosing (CV 18.5%) and fixed dose of 900 mg with 25% dose reduction, if the eGFR<60 mL/min (CV: 19.1%), resulted in less interindividual variability of AUC. CONCLUSIONS Higher exposure to pemetrexed does not increase PFS/OS but is significantly associated with increased occurrence of severe toxicity. Our findings suggest that fixed dosing reduces interpatient pharmacokinetic variability and thereby might prevent toxicity, while preserving effectiveness.
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Affiliation(s)
- S Visser
- Department of Pulmonary Medicine, Amphia Hospital, Breda, Netherlands; Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
| | - S L W Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands; Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, Netherlands
| | - P de Bruijn
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - H N A Belderbos
- Department of Pulmonary Medicine, Amphia Hospital, Breda, Netherlands
| | - R Cornelissen
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - R H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - B H Stricker
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands; Inspectorate of Health Care, Utrecht, Netherlands
| | - J G J V Aerts
- Department of Pulmonary Medicine, Amphia Hospital, Breda, Netherlands; Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
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Yumioka T, Honda M, Nishikawa R, Teraoka S, Kimura Y, Iwamoto H, Morizane S, Hikita K, Takenaka A. Sarcopenia as a significant predictive factor of neutropenia and overall survival in urothelial carcinoma patients underwent gemcitabine and cisplatin or carboplatin. Int J Clin Oncol 2019; 25:158-164. [DOI: 10.1007/s10147-019-01544-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 09/03/2019] [Indexed: 10/26/2022]
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de Man FM, Veerman GM, Oomen-de Hoop E, Deenen MJ, Meulendijks D, Mandigers CM, Soesan M, Schellens JH, van Meerten E, van Gelder T, Mathijssen RH. Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine. Ther Adv Med Oncol 2019; 11:1758835919838964. [PMID: 31019570 PMCID: PMC6466460 DOI: 10.1177/1758835919838964] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/28/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Capecitabine is generally dosed based on body surface area (BSA). This dosing strategy has several limitations; however, evidence for alternative strategies is lacking. Therefore, we analyzed the toxicity and effectiveness of fixed-dose capecitabine and compared this strategy with a BSA-based dose of capecitabine in a large set of patients. METHODS Patients treated with fixed-dose capecitabine between 2003 and 2015 were studied. A comparable group of patients, dosed based on BSA, was chosen as a control cohort. A total of two combined scores were used: capecitabine-specific toxicity (diarrhea, National Cancer Institute Common Toxicity Criteria grade ⩾3, hand-foot syndrome ⩾2, or neutropenia ⩾2), and clinically relevant events due to toxicity, that is, hospital admission, dose reduction, or discontinuation. Per treatment regimen, patients were divided into three BSA groups based on BSA quartiles corrected for sex. Toxicity scores were compared by a Chi-square test between cohorts, and within cohorts using BSA groups. Progression-free survival (PFS) was estimated by the Kaplan-Meier method. RESULTS A total of 2319 patients were included (fixed dosed, n = 1126 and BSA-based dose, n = 1193). Overall, four regimens were evaluated: capecitabine-radiotherapy (n = 1178), capecitabine-oxaliplatin (n = 519), capecitabine triplet (n = 181) and capecitabine monotherapy (n = 441). The incidence of capecitabine-specific toxicity and clinically relevant events was comparable between fixed-dose and BSA-dosed patients, while a small difference (7.1%) in absolute dose was found. Both cohorts showed only a higher incidence of both toxicity scores in the lowest BSA group of the capecitabine-radiotherapy group (p < 0.05). Subgroups of the fixed-dose cohort analyzed for PFS, showed no differences between BSA groups. CONCLUSIONS Fixed-dose capecitabine is as comparably well tolerated and effective as BSA-based dosing and could be considered as a reasonable alternative for BSA-based dosing.
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Affiliation(s)
- Femke M. de Man
- Department of Medical Oncology, Erasmus MC
Cancer Institute, PO Box 2040, 3000 CA Rotterdam, the Netherlands
| | - G.D. Marijn Veerman
- Department of Medical Oncology, Erasmus MC
Cancer Institute, Rotterdam, the Netherlands
| | - Esther Oomen-de Hoop
- Department of Medical Oncology, Erasmus MC
Cancer Institute, Rotterdam, the Netherlands
| | - Maarten J. Deenen
- Department of Clinical Pharmacy, Catharina
Hospital, Eindhoven, the Netherlands
- Department of Clinical Pharmacy and Toxicology,
Leiden University Medical Center, Leiden, the Netherlands
| | | | | | - Marcel Soesan
- Department of Internal Medicine, Slotervaart
Hospital, Amsterdam, the Netherlands
| | - Jan H.M. Schellens
- Department of Clinical Pharmacology, Division of
Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the
Netherlands
- Utrecht Institute for Pharmaceutical Sciences,
Utrecht University, Utrecht, the Netherlands
| | - Esther van Meerten
- Department of Medical Oncology, Erasmus MC
Cancer Institute, Rotterdam, the Netherlands
| | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus
University Medical Center, Rotterdam, the Netherlands
| | - Ron H.J. Mathijssen
- Department of Medical Oncology, Erasmus MC
Cancer Institute, Rotterdam, the Netherlands
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Robins HI, Eickhoff J, Gilbert MR, Armstrong TS, Shi W, De Groot JF, Schultz CJ, Hunter GK, Valeinis E, Roach M, Youssef EF, Souhami L, Howard SP, Lieberman FS, Herman JG, Zhang P, Mehta MP. The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525. Neurooncol Pract 2019; 6:473-478. [PMID: 31832217 DOI: 10.1093/nop/npz006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m2 may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m2 was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed. Methods The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. Obesity was defined as a BMI ≥30. Results There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, P < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) P = .009 in spite of the lack of association between gender and BSA or BMI. Conclusion TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.
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Affiliation(s)
- H Ian Robins
- University of Wisconsin Hospital and Clinics, Madison
| | - Jens Eickhoff
- University of Wisconsin Hospital and Clinics, Madison
| | - Mark R Gilbert
- National Institutes of Health Clinical Center Neuro-Oncology Branch, Bethesda, MD
| | | | - Wenyin Shi
- Thomas Jefferson University Hospital, Philadelphia, PA
| | | | | | | | - Egils Valeinis
- Pauls Stradiņš Clinical University Hospital, Riga, Latvia
| | - Mack Roach
- University of California San Francisco Medical Center-Mount Zion
| | | | - Luis Souhami
- McGill University Health Centre, Montreal, Québec, Canada
| | | | | | | | - Peixin Zhang
- NRG Oncology Statistics and Data Management Center, Philadelphia, PA
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Beumer JH, Chu E, Allegra C, Tanigawara Y, Milano G, Diasio R, Kim TW, Mathijssen RH, Zhang L, Arnold D, Muneoka K, Boku N, Joerger M. Therapeutic Drug Monitoring in Oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5-Fluorouracil Therapy. Clin Pharmacol Ther 2019; 105:598-613. [PMID: 29923599 PMCID: PMC6309286 DOI: 10.1002/cpt.1124] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 05/09/2018] [Indexed: 12/14/2022]
Abstract
5-Fluorouracil (5-FU) is dosed by body surface area, a practice unable to reduce the interindividual variability in exposure. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), we evaluated clinical evidence and strongly recommend TDM for the management of 5-FU therapy in patients with colorectal or head-and-neck cancer receiving common 5-FU regimens. Our systematic methodology provides a framework to evaluate published evidence in support of TDM recommendations in oncology.
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Affiliation(s)
- Jan H. Beumer
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Edward Chu
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | - Yusuke Tanigawara
- Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo, Japan
| | - Gerard Milano
- Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France
| | - Robert Diasio
- Developmental Therapeutics Program, Mayo Clinic Cancer Center, Rochester, MN
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic School of Medicine, Rochester, MN, USA
| | - Tae Won Kim
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Ron H. Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Li Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dirk Arnold
- Department of Oncology, AK Altona, Asklepios Tumorzentrum Hamburg, Hamburg, Germany
| | - Katsuki Muneoka
- Division of Oncology Center, Niitsu Medical Center Hospital, Niigata City, Japan
| | - Narikazu Boku
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan
| | - Markus Joerger
- Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland
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Tjokrowidjaja A, Hovey E, Lewis CR. Let's talk about cytotoxic chemotherapy dosing: unravelling adjustments and off-protocol prescribing. Med J Aust 2019; 210:65-66. [PMID: 30712300 DOI: 10.5694/mja2.12072] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
| | - Elizabeth Hovey
- Prince of Wales Hospital and Community Health Services, Sydney, NSW.,Prince of Wales Clinical School, University of New South Wales, Sydney, NSW
| | - Craig R Lewis
- Prince of Wales Hospital and Community Health Services, Sydney, NSW.,Prince of Wales Clinical School, University of New South Wales, Sydney, NSW
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Gupta N, Hanley MJ, Diderichsen PM, Yang H, Ke A, Teng Z, Labotka R, Berg D, Patel C, Liu G, van de Velde H, Venkatakrishnan K. Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor. Clin Pharmacol Ther 2019; 105:376-387. [PMID: 29446068 PMCID: PMC6585617 DOI: 10.1002/cpt.1047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 01/26/2018] [Accepted: 02/12/2018] [Indexed: 12/27/2022]
Abstract
Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib.
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Affiliation(s)
- Neeraj Gupta
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Michael J. Hanley
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | | | - Huyuan Yang
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Alice Ke
- Certara USA, Inc.PrincetonNew JerseyUSA
| | - Zhaoyang Teng
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Richard Labotka
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Deborah Berg
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Chirag Patel
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Guohui Liu
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Helgi van de Velde
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Karthik Venkatakrishnan
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
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Albert-Marí A, Valero-García S, Fornés-Ferrer V, Poveda-Andrés JL. Exploratory analysis for the implementation of antineoplastic logarithmic dose banding. Int J Clin Pharm 2018; 40:1281-1291. [DOI: 10.1007/s11096-018-0714-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/03/2018] [Indexed: 11/28/2022]
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Étude comparative de coûts entre les poches de gemcitabine prêtes à l’emploi et une fabrication en unité de reconstitution. Bull Cancer 2018; 105:679-685. [DOI: 10.1016/j.bulcan.2018.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/20/2018] [Accepted: 05/24/2018] [Indexed: 11/18/2022]
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Takehara H, Kanda Y, Ichiki T. Microfluidic Model for Optical Detection of Nanoparticles in Whole Blood. J PHOTOPOLYM SCI TEC 2018. [DOI: 10.2494/photopolymer.31.59] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Hiroaki Takehara
- Department of Materials Engineering, School of Engineering, The University of Tokyo
| | - Yukihiro Kanda
- Department of Materials Engineering, School of Engineering, The University of Tokyo
| | - Takanori Ichiki
- Department of Materials Engineering, School of Engineering, The University of Tokyo
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Impact of race on dose selection of molecular-targeted agents in early-phase oncology trials. Br J Cancer 2018; 118:1571-1579. [PMID: 29795308 PMCID: PMC6008299 DOI: 10.1038/s41416-018-0102-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/11/2018] [Indexed: 01/01/2023] Open
Abstract
Background We examined the impact of race on the maximum tolerated doses (MTD) and final approved doses (FAD) of single-agent molecular-targeted agents (MTA) in North America/Europe (NA/EU) and Asia. Methods We searched PubMed and regulatory databases to identify targeted drugs approved globally and compared their FAD and MTD in corresponding phase I/II studies conducted separately in NA/EU and Asia. To evaluate this further, we conducted parallel, prospective, first-in-human studies of DS-7423, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumours in the US and Japan. We pooled and compared the pharmacokinetics (PK), pharmacodynamics (PD), toxicity, and efficacy between these populations. Results 17 MTA were approved in NA/EU and Asia from 2001 to 2015. Recommended phase 2 doses (RP2D) were identical across races in 14 of 17 (80%) studies and differences were not clinically meaningful. FAD were identical across all regions. 42 and 27 patients from US and Japan, respectively, were enrolled in the phase I studies of DS-7423. Despite differences in race, body weight, and body mass index, the RP2D were 240 mg/day with no differences in toxicities, PK, PD, or efficacy. Conclusions Conducting separate clinical trials of single-agent MTA in Caucasian and Asian populations may be redundant.
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White-Koning M, Osborne C, Paci A, Boddy AV, Chatelut E, Veal GJ. Investigating the potential impact of dose banding for systemic anti-cancer therapy in the paediatric setting based on pharmacokinetic evidence. Eur J Cancer 2018; 91:56-67. [PMID: 29335155 PMCID: PMC5811050 DOI: 10.1016/j.ejca.2017.11.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 10/04/2017] [Accepted: 11/27/2017] [Indexed: 01/09/2023]
Abstract
Background To make systemic anti-cancer therapy (SACT) preparation more practicable, dose-banding approaches are currently being introduced in many clinical centres. The present study aimed to determine the potential impact of using recently developed National Health Service in England (NHSE) dose-banding tables in a paediatric setting. Methods Using pharmacokinetic parameters obtained from 385 drug administrations in 352 children aged from 1 month to 18 years, treated with five drugs (dactinomycin, busulfan, carboplatin, cyclophosphamide and etoposide), individual exposures (area under the plasma drug concentration versus time curve; AUC) obtained using doses rounded according to the published NHSE tables were calculated and compared with those obtained by standard dose calculation methods. Results For all five drugs, the relative variation between the NHSE dose and the recommended dose (RecDose) (standard individually calculated dose) was between −6% and +5% as expected. In terms of AUC, there was no statistically significant difference in precision between exposures obtained by the RecDose and those obtained with dose banding (absolute value of relative difference 15–34%). Conclusion Based on pharmacokinetic data for these five drugs, the results generated support the implementation of NHSE dose-banding tables. Indeed, inter-patient variability in drug clearance and exposure far outweighs the impact of relatively small drug dose changes associated with dose banding.
The potential impact of using dose-banding tables in the setting of childhood cancer has been investigated. In 352 children receiving five anticancer drugs no difference was found in exposures using dose banding or recommended doses. Results generated support the implementation of National Health Service in England dose-banding tables.
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Affiliation(s)
- Melanie White-Koning
- CRCT (Cancer Research Centre of Toulouse), Université de Toulouse, Inserm UMR 1037, Université Paul Sabatier, 31059 Toulouse Cedex 9, France.
| | - Caroline Osborne
- Pharmacy Department, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK
| | - Angelo Paci
- UMR CNRS 8203, Institut Gustave Roussy, 94805 Villejuif Cedex, France
| | - Alan V Boddy
- Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia
| | - Etienne Chatelut
- CRCT (Cancer Research Centre of Toulouse), Université de Toulouse, Inserm UMR 1037, Université Paul Sabatier, 31059 Toulouse Cedex 9, France; Institut Claudius Regaud, Institut Universitaire Du Cancer Toulouse-Oncopole, 31059 Toulouse Cedex 9, France
| | - Gareth J Veal
- Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
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Schmidinger M, Danesi R, Jones R, McDermott R, Pyle L, Rini B, Négrier S. Individualized dosing with axitinib: rationale and practical guidance. Future Oncol 2017; 14:861-875. [PMID: 29264944 DOI: 10.2217/fon-2017-0455] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the 'flexible dosing' method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety.
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Affiliation(s)
- Manuela Schmidinger
- Clinical Division of Oncology, Department of Medicine I & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Romano Danesi
- Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy
| | - Robert Jones
- Institute of Cancer Sciences, University of Glasgow, The Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - Ray McDermott
- Department of Medical Oncology, St Vincent's University Hospital & The Adelaide & Meath Hospital, Dublin, Ireland
| | - Lynda Pyle
- Renal Cancer Unit, Department of Medicine, Royal Marsden Hospital, London, UK
| | - Brian Rini
- Department of Hematology & Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
| | - Sylvie Négrier
- Medical Oncology Department, University of Lyon, Centre Léon Bérard, Lyon, France
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Hidalgo M, Martinez-Garcia M, Le Tourneau C, Massard C, Garralda E, Boni V, Taus A, Albanell J, Sablin MP, Alt M, Bahleda R, Varga A, Boetsch C, Franjkovic I, Heil F, Lahr A, Lechner K, Morel A, Nayak T, Rossomanno S, Smart K, Stubenrauch K, Krieter O. First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors. Clin Cancer Res 2017; 24:1536-1545. [PMID: 29217526 DOI: 10.1158/1078-0432.ccr-17-1588] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 10/23/2017] [Accepted: 11/30/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies.Experimental Design: Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control.Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation.Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536-45. ©2017 AACR.
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Affiliation(s)
- Manuel Hidalgo
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. .,START Madrid-CIOCC, HM Sanchinarro, Madrid, Spain
| | | | | | | | | | | | - Alvaro Taus
- Medical Oncology Department, Hospital del Mar., Barcelona, Spain
| | - Joan Albanell
- Medical Oncology Department, Hospital del Mar., Barcelona, Spain
| | - Marie-Paule Sablin
- Department of Medical Oncology, Institut Curie, Saint-Cloud and Paris, France
| | - Marie Alt
- Department of Medical Oncology, Institut Curie, Saint-Cloud and Paris, France
| | - Ratislav Bahleda
- Department of Drug Development, Gustave Roussy, Villejuif, France
| | - Andrea Varga
- Department of Drug Development, Gustave Roussy, Villejuif, France
| | | | | | - Florian Heil
- Roche Innovation Center Munich, Penzberg, Germany
| | | | | | | | - Tapan Nayak
- Roche Innovation Center Basel, Basel, Switzerland
| | | | - Kevin Smart
- Roche Innovation Center Welwyn, Welwyn Garden City, United Kingdom
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Reck M. Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Immunotherapy 2017; 10:93-105. [PMID: 29145737 DOI: 10.2217/imt-2017-0121] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
This review describes trials evaluating the monoclonal antibody pembrolizumab (an immunotherapy that blocks the interaction between programmed death-1 and programmed death-ligand 1 and 2 [PD-L1/PD-L2]) as first-line therapy for advanced non-small-cell lung cancer (NSCLC). In the Phase III KEYNOTE-024 study, pembrolizumab monotherapy significantly improved progression-free survival (primary end point) and overall survival, and was associated with fewer adverse events compared with platinum-based chemotherapy in patients with NSCLC with PD-L1 expression on ≥50% of tumor cells. In cohort G of the Phase I/II KEYNOTE-021 study, pembrolizumab plus pemetrexed and carboplatin significantly improved objective response rate (primary end point) and progression-free survival versus pemetrexed and carboplatin alone, and had manageable toxicity in patients with nonsquamous NSCLC. These results have changed first-line management of advanced NSCLC.
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Affiliation(s)
- Martin Reck
- Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center of Lung Research (DZL), Grosshansdorf, Germany
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