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dc.contributor.authorPingeon, Marine
dc.date.accessioned2020-05-29T23:16:13Z
dc.date.available2020-05-29T23:16:13Z
dc.date.issued2019-07-25
dc.identifier.urihttp://elea.unisa.it:8080/xmlui/handle/10556/4509
dc.description2017 - 2018it_IT
dc.description.abstractThe U.S. Food and Drug Administration defines as Precision or Personalized Medicine (PM) an innovative therapeutic approach that tailors therapy and prevention on patients based on inter-individual variabilities in molecular or environmental features and in lifestyles. The major goals of PM are to maximize treatment efficacy and to reduce cost, toxicities and therapy failure rates by early identification of patients who might benefit or not of a specific treatment. In this scenario, therapeutic drug monitoring (TDM) is an important laboratory tool for PM because of the possibility to measure several drugs and bioactive molecules in human biological matrices. TDM is based on the hypothesis that in the majority of drugs, there is a relationship between administered dose and circulating concentration of unbound fraction - and between this concentration and observed pharmacological effects. TDM is recommended for drugs with significant inter-individual pharmacokinetic variability and an established relationship between blood concentrations and clinical efficacy and/or toxicity. Moreover, TDM is also advisable in special populations such as pregnant women and children. To date, liquid chromatography and immunometric assay are still considered the standard for molecule measurement in biological fluids; however, in recent years, LC tandem mass spectrometry (LC-MS) is gaining popularity because of the possibility of in-depth and multiplexed analysis with high selectivity and specificity. During this Ph.D. program, we developed several high performance LC (HPLC)- and LC-MS/MS-based approaches for TDM of different drugs measured in various types of body fluids and validated according to EMA and FDA guidelines. In particular, we focused on: 1) TDM of hydroxychloroquine (HCQ) blood concentration, a drug with a wide therapeutic window. Our method was validated on a cohort of patients with Systemic Lupus Erythematosus treated with HCQ and blood concentrations were correlated to several clinical parameters, such quality of life. Moreover, TDM of HCQ was also used to monitor treatment adherence in those subjects. 2) TDM of a commonly used chemotherapeutic agent, the 5-fluorouracil (5-FU), which is known to have a narrow therapeutic window and a high toxicity 3) TDM of a new kinase inhibitor, Ruxolitinib, approved for the treatment of myeloproliferative hematologic disorders. 4) TDM of several drugs, such as caffeine and phenobarbital, in newborns who are at particular risk of uncorrected drug dosage. Due to the need to carry out analyses on very-small volume samples, we validated an analytical method using micro-sampling techniques such as the dried blood spot (DBS) sampling combined with LC-MS/MS analysis. [edited by author]it_IT
dc.language.isoenit_IT
dc.publisherUniversita degli studi di Salernoit_IT
dc.subjectHPLCit_IT
dc.subjectLC-DS/MSit_IT
dc.subjectTDMit_IT
dc.titleDevelopment and validation of analytical methods for therapeutic drug monitoringit_IT
dc.typeDoctoral Thesisit_IT
dc.subject.miurBIO/10 BIOCHIMICAit_IT
dc.contributor.coordinatoreMonteleone, Palmieroit_IT
dc.description.cicloXVII n.s. (XXXI ciclo)it_IT
dc.contributor.tutorIzzo, Vivianait_IT
dc.identifier.DipartimentoMedicina, Chirurgia e Odontoiatriait_IT
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