Utility of Therapeutic Drug Monitoring of Imatinib,Nilotinib, and Dasatinib in Chronic Myeloid Leukemia: A Systematic Review and Meta-analysis |
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| Institution: | 1. Department of Radiology, Hospital Universitario Virgen del Rocío, Seville, Spain;2. Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain;3. UICEC Hospital Universitario de La Princesa, Plataforma Spanish Clinical Research Network, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain;4. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain;1. Department of Pharmacy, Uppsala University, Husargatan 3, SE-751 23 Uppsala, Sweden;2. XSpray Microparticles AB, Gunnar Asplunds Allé 32, SE-171 63 Solna, Sweden;3. Division of Analytical Pharmaceutical Chemistry, Uppsala University, Husargatan 3, SE-751 23 Uppsala, Sweden;4. SP Technical Research Institute of Sweden, Chemistry, Materials and Surfaces, Brinellgatan 4, SE-504 62 Borås, Sweden;5. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark;1. Department of Oncology, Sichuan Provincial People''s Hospital, University of Electronic Science and Technology of China, Chengdu, China;2. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China;1. Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria;2. Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;3. Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Austria;4. Department of Laboratory Medicine, Medical University of Vienna, Austria;5. Department of Internal Medicine II, Division of Angiology, Medical University of Vienna, Austria;6. Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Austria;7. Medical Clinic III for Oncology, Haematology, Immunology and Rheumatology, University Hospital Bonn (UKB), Germany;1. Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy;2. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy;3. Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology, University of Bologna, Bologna, Italy;1. Department of Pharmacy, Akita University Hospital, Akita, Japan;2. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan;1. Department of Medicine and Surgery, University of Insubria, Varese, Italy;2. Department of Medical Oncology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy;3. Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy |
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| Abstract: | PurposeThis study examined the utility of therapeutic drug monitoring (TDM) of imatinib, nilotinib, and dasatinib in adult patients with chronic-phase chronic myeloid leukemia (CML). TDM in CML entails the measurement of plasma tyrosine kinase inhibitor (TKI) concentration to predict efficacy and tolerability outcomes and to aid in clinical decision making. TDM was to be deemed useful if it could be used for predicting the effectiveness of a drug and/or the occurrence of adverse reactions. It was expected that the findings from the present study would allow for the definition of a therapeutic range of each TKI.MethodsA systematic review of studies reporting trough TKI levels (Cmin) and clinical outcomes was performed. We included randomized clinical trials, nonrandomized controlled studies, interrupted time series studies, and case series studies that provided information about plasma levels of imatinib, nilotinib, or dasatinib and relevant clinical end points in adult patients with chronic-phase CML treated with the corresponding TKI as the single antiproliferative therapy. Meta-analyses, Student t tests, and receiver operating characteristic analyses were performed to detect mean differences between groups of patients with or without: (1) the achievement of major molecular response and (2) adverse reactions.FindingsA total of 38 studies (28 for imatinib, 7 for nilotinib, and 3 for dasatinib) were included in the systematic review. TDM was found useful in predicting the efficacy of imatinib, with a Cmin cutoff value of 1000 ng/mL, consistent with guideline recommendations. We suggest a therapeutic range of imatinib at a Cmin of 1000–1500 ng/mL because higher concentrations did not increase efficacy. The findings from the rest of the comparisons were inconclusive.ImplicationsTDM is useful in predicting the efficacy of imatinib in CML. Further research is needed to determine its validity with nilotinib and dasatinib. |
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| Keywords: | chronic myeloid leukemia dasatinib imatinib nilotinib therapeutic drug monitoring tyrosine kinase inhibitor |
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