On-Site Therapeutic Drug Monitoring
2020; Elsevier BV; Volume: 38; Issue: 11 Linguagem: Inglês
10.1016/j.tibtech.2020.03.001
ISSN0167-9430
AutoresH. Ceren Ates, Jason Roberts, Jeffrey Lipman, Anthony E. G. Cass, G. Urban, Can Dincer,
Tópico(s)Microfluidic and Capillary Electrophoresis Applications
ResumoOn-site therapeutic drug monitoring has the potential to improve patient outcomes and drastically reduce healthcare costs.Despite being on the radar of the scientific community for almost two decades, sensor-based approaches have yet to break through and support the clinical application of therapeutic drug monitoring, potentially due to the gap between scientific and clinical communities.Chromatography as a routine practice is limited due to its lack of standardization, high turnaround-times and instrumentation costs, and labored sample preparation.Sensors offer a low-cost, easy-to-use, and on-site analysis method to explore the full potential of therapeutic drug monitoring, overcoming these limitations.The success of individualized dosing strongly relies on two factors: how PK/PD studies are integrated with therapeutic drug monitoring and how the measurement process is managed. Recent technological advances have stimulated efforts to bring personalized medicine into practice. Yet, traditional application fields like therapeutic drug monitoring (TDM) have remained rather under-appreciated. Owing to clear dose-response relationships, TDM could improve patient outcomes and reduce healthcare costs. While chromatography-based routine practices are restricted due to high costs and turnaround times, biosensors overcome these limitations by offering on-site analysis. Nevertheless, sensor-based approaches have yet to break through for clinical TDM applications, due to the gap between scientific and clinical communities. We provide a critical overview of current TDM practices, followed by a TDM guideline to establish a common ground across disciplines. Finally, we discuss how the translation of sensor systems for TDM can be facilitated, by highlighting the challenges and opportunities. Recent technological advances have stimulated efforts to bring personalized medicine into practice. Yet, traditional application fields like therapeutic drug monitoring (TDM) have remained rather under-appreciated. Owing to clear dose-response relationships, TDM could improve patient outcomes and reduce healthcare costs. While chromatography-based routine practices are restricted due to high costs and turnaround times, biosensors overcome these limitations by offering on-site analysis. Nevertheless, sensor-based approaches have yet to break through for clinical TDM applications, due to the gap between scientific and clinical communities. We provide a critical overview of current TDM practices, followed by a TDM guideline to establish a common ground across disciplines. Finally, we discuss how the translation of sensor systems for TDM can be facilitated, by highlighting the challenges and opportunities. Developments, particularly in the past 50 years (Box 1), have made it clear that the concentration of a drug in blood is correlated to the pharmacological activity, so concentration is a better candidate than dosage for quantifying efficacy or toxicity. TDM is the clinical practice of measuring this drug concentration in blood or plasma, or in other biological fluids that can be linked to blood drug concentrations. This measured drug concentration is then used to adjust the drug dosing regimen by targeting a predefined concentration or exposure interval, called a therapeutic range. Hence, the reliability of TDM is strongly related to the specificity and sensitivity of the analysis method. In the contemporary context of clinical TDM, these tests are performed by using either chromatographic methods coupled with special detectors (often mass spectrometers) or immunoassays. Nevertheless, these traditional methods have some practical limitations for the envisioned large-scale, distributed TDM practice, such as lack of standardization in workflows, long turnaround times, and high instrumentation costs with complex sample preparation. In this regard, new developments in sensing technologies offer a unique opportunity to overcome these limitations and to explore the full potential of TDM. Recent advances and the current capabilities of such applications have been well addressed in several recent reviews [1.Shafiee A. et al.Nanosensors for therapeutic drug monitoring: implications for transplantation.Nanomedicine. 2019; 14: 2735-2747Crossref PubMed Scopus (2) Google Scholar, 2.McKeating K.S. et al.Biosensors and nanobiosensors for therapeutic drug and response monitoring.Analyst. 2016; 141: 429-449Crossref PubMed Google Scholar, 3.Carlier M. et al.Assays for therapeutic drug monitoring of β-lactam antibiotics: a structured review.Int. J. Antimicrob. Agents. 2015; 46: 367-375Crossref PubMed Google Scholar, 4.Meneghello A. et al.Biosensing technologies for therapeutic drug monitoring.Curr. Med. Chem. 2017; 25: 4354-4377Crossref Scopus (11) Google Scholar]. Nonetheless, these novel technologies are failing to diffuse rapidly into clinical practice, unlike their predecessors from the 1960s and 1970s. In order to understand the reasons behind this translation problem, which is the focus of this review, we first explain different notions of drug monitoring and discuss current trends by providing an overview of recent TDM studies in both clinical and scientific contexts, particularly focusing on studies that have worked with human samples in the past 5 years. Then, we present a guideline on how to establish a complete TDM practice, followed by a discussion on the conceptual differences between frontline players (clinicians) and technology or model developers (the scientific community) and how this difference is reflected in their modus operandi (Figure 1, Key Figure).Box 1Historical Perspectives on TDMThe notion of personalized medicine and on-site treatment is as old as human civilization. Even hunter-gatherer microsocieties were aware of the fauna and flora surrounding them and healers offered the best medicine in their arsenal to those seeking help [75.Diamond J. Guns, Germs, and Steel: The Fates of Human Societies. W.W. Norton, 1997Google Scholar]. The earliest examples of drug therapy from antiquity include Sumerian clay tablets (2000 BCE), the Ebers Papyrus (1550 BCE), the Sushruta Samhita (600 BCE), De materia medica (50–70 CE), Shennong Bencao Jing (200 CE), and many others. The basic principle of treatment remained more or less the same for thousands of years until the 19th century, the age of synthetic chemistry. As scientists developed systematic ways to design the structure of organic substances at will, local apothecaries offering personalized remedies were replaced by industrialized 'one-size-fits-all' mass production. Nevertheless, this paradigmatic idea is now being challenged with a revolution arising from developments in electronics, data science, manufacturing technology, and process control over the past century.The critical role of dosage has been long known for patients hovering between life (efficacy) and death (either toxicity or subtherapeutic exposure) since antiquity. As Paracelsus put it, 'All things are poison and nothing is without poison; only the dose makes a thing not a poison'. The ability to monitor and correlate this transition, however, was first demonstrated in 1932 by Widmark [76.Widmark E.M. Die theoretischen Grundlagen und die praktische Verwendbarkeit der gerichtlich-medizinischen Alkoholbestimmung.J. Am. Med. Assoc. 1932; 98: 1834Crossref Google Scholar] (Figure I). In the following decades, concerns about the 'one-size-fits-all' approach began to appear in scientific communities, supported by blood concentration measurements for several drugs. In the 1960s, the first PK study was published and the importance of PK was established [77.Nelson E. Kinetics of drug absorption, distribution, metabolism, and excretion.J. Pharm. Sci. 1961; 50: 181-192Abstract Full Text PDF PubMed Google Scholar]. Another historically important landmark was a paper from 1965, the first structured review on the importance of 'monitoring of drugs' [78.Finney D.J. The design and logic of a monitor of drug use.J. Chronic Dis. 1965; 18: 77-98Abstract Full Text PDF PubMed Google Scholar]. These investigations gained further momentum with developments in chromatographic techniques. The following years were a golden age of drug monitoring. Concentrations of various drugs were measured by using first gas chromatography (GC) then HPLC, and mass spectrometry (MS). Another substantial milestone was the introduction of immunoassays, which revolutionized the concept by increasing feasibility of performing assays [79.Horning M. et al.Use of saliva in therapeutic drug monitoring.Clin. Chem. 1977; 23: 157-164Crossref PubMed Google Scholar]. Simultaneously, previously proposed notions, such as dose-toxicity relationships, PK, and drug–protein binding, were being investigated extensively, which eventually led to optimization of sampling strategies and analytical workflows. The 1990s onwards saw the introduction of more sophisticated chromatographic techniques, software packages to design dosage regimens, the concept of noninvasive and minimally invasive methods, wearable sensors, and feedback-controlled smart drug delivery systems.Figure 1Key Figure. Overview of Therapeutic Drug Monitoring (TDM).Show full captionTDM should include the active management of free drug concentrations in human body fluids using either chromatographic or immunoassay-based methods or on-site solutions (sensors and wearables) for the optimum benefit of each individual patient.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The notion of personalized medicine and on-site treatment is as old as human civilization. Even hunter-gatherer microsocieties were aware of the fauna and flora surrounding them and healers offered the best medicine in their arsenal to those seeking help [75.Diamond J. Guns, Germs, and Steel: The Fates of Human Societies. W.W. Norton, 1997Google Scholar]. The earliest examples of drug therapy from antiquity include Sumerian clay tablets (2000 BCE), the Ebers Papyrus (1550 BCE), the Sushruta Samhita (600 BCE), De materia medica (50–70 CE), Shennong Bencao Jing (200 CE), and many others. The basic principle of treatment remained more or less the same for thousands of years until the 19th century, the age of synthetic chemistry. As scientists developed systematic ways to design the structure of organic substances at will, local apothecaries offering personalized remedies were replaced by industrialized 'one-size-fits-all' mass production. Nevertheless, this paradigmatic idea is now being challenged with a revolution arising from developments in electronics, data science, manufacturing technology, and process control over the past century. The critical role of dosage has been long known for patients hovering between life (efficacy) and death (either toxicity or subtherapeutic exposure) since antiquity. As Paracelsus put it, 'All things are poison and nothing is without poison; only the dose makes a thing not a poison'. The ability to monitor and correlate this transition, however, was first demonstrated in 1932 by Widmark [76.Widmark E.M. Die theoretischen Grundlagen und die praktische Verwendbarkeit der gerichtlich-medizinischen Alkoholbestimmung.J. Am. Med. Assoc. 1932; 98: 1834Crossref Google Scholar] (Figure I). In the following decades, concerns about the 'one-size-fits-all' approach began to appear in scientific communities, supported by blood concentration measurements for several drugs. In the 1960s, the first PK study was published and the importance of PK was established [77.Nelson E. Kinetics of drug absorption, distribution, metabolism, and excretion.J. Pharm. Sci. 1961; 50: 181-192Abstract Full Text PDF PubMed Google Scholar]. Another historically important landmark was a paper from 1965, the first structured review on the importance of 'monitoring of drugs' [78.Finney D.J. The design and logic of a monitor of drug use.J. Chronic Dis. 1965; 18: 77-98Abstract Full Text PDF PubMed Google Scholar]. These investigations gained further momentum with developments in chromatographic techniques. The following years were a golden age of drug monitoring. Concentrations of various drugs were measured by using first gas chromatography (GC) then HPLC, and mass spectrometry (MS). Another substantial milestone was the introduction of immunoassays, which revolutionized the concept by increasing feasibility of performing assays [79.Horning M. et al.Use of saliva in therapeutic drug monitoring.Clin. Chem. 1977; 23: 157-164Crossref PubMed Google Scholar]. Simultaneously, previously proposed notions, such as dose-toxicity relationships, PK, and drug–protein binding, were being investigated extensively, which eventually led to optimization of sampling strategies and analytical workflows. The 1990s onwards saw the introduction of more sophisticated chromatographic techniques, software packages to design dosage regimens, the concept of noninvasive and minimally invasive methods, wearable sensors, and feedback-controlled smart drug delivery systems. TDM should include the active management of free drug concentrations in human body fluids using either chromatographic or immunoassay-based methods or on-site solutions (sensors and wearables) for the optimum benefit of each individual patient. Although chromatography (Box 2) has been successfully implemented in clinical studies, there are still many challenges that are needed to be addressed in liquid chromatography with tandem mass spectrometry (LC-MS/MS) (see Glossary) methods. Despite its high specificity, matrix interference may lead to falsely low or high results; that is, the matrix and co-eluting compounds can interfere with the ionization process in MS (via ion suppression/enhancement) [5.Mika A. Stepnowski P. Current methods of the analysis of immunosuppressive agents in clinical materials: a review.J. Pharm. Biomed. Anal. 2016; 127: 207-231Crossref PubMed Scopus (24) Google Scholar]. Furthermore, the throughput of LC-MS/MS is lower than that of the conventional immunoassay platforms. Recent studies are either addressing these issues [6.Decosterd L.A. et al.The emerging role of multiplex tandem mass spectrometry analysis for therapeutic drug monitoring and personalized medicine.Trends Anal. Chem. 2016; 84: 5-13Crossref Scopus (3) Google Scholar,7.Sime F.B. et al.Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2014; 960: 134-144Crossref PubMed Scopus (0) Google Scholar] or exploiting or improving this method's inherent advantages [8.Lindner J.M. et al.A semi-automated, isotope-dilution high-resolution mass spectrometry assay for therapeutic drug monitoring of antidepressants.Clin. Mass Spectrom. 2019; 14: 89-98Crossref Scopus (1) Google Scholar,9.Bhatnagar A. et al.Quantitation of the anticancer drug abiraterone and its metabolite Δ(4)-abiraterone in human plasma using high-resolution mass spectrometry.J. Pharm. Biomed. Anal. 2018; 154: 66-74Crossref PubMed Scopus (5) Google Scholar].Box 2ChromatographyThe basic principle of all chromatographic methods is the separation of unknown components within a mobile phase by hindering the relative mobility of each molecule by interactions between the eluent and the stationary phase. The mobile phase can be a gas, supercritical fluid, organic solvent, or ionic liquid. As the eluents leave the separation column at their respective retention times, compounds are identified using a variety of techniques with different complexities, such as UV/Vis spectrophotometry, refractive index, DAD, FID, and MS. The selection of mobile and stationary phases is the most critical parameter as they determine the success rate of adequate resolution of individual compound peaks.The very first junction in the decision-making process is the choice between GC and LC. Although GC ensures high resolution, it requires the compounds to be gaseous or intrinsically volatile, or have a volatile derivative. Therefore, only about 20% of the organic compounds are separable via GC. Conversely, LC can be used for a wide range of compounds without the need for derivatization, which makes it amenable for at least 80% of the candidate compounds. This is why LC methods such as HPLC are usually the methods of choice in clinical laboratories, except for the few cases where LC is not suitable. The second decision is the type of detector coupled with the chromatography method. A variety of detectors are utilized in different fields, yet LC-MS/MS has been preferred in both reference and clinical laboratories for more than two decades due to its superior specificity and sensitivity over conventional immunoassays, the possibility of processing multiple analytes, and smaller sample volume requirements [6.Decosterd L.A. et al.The emerging role of multiplex tandem mass spectrometry analysis for therapeutic drug monitoring and personalized medicine.Trends Anal. Chem. 2016; 84: 5-13Crossref Scopus (3) Google Scholar,94.Shipkova M. Svinarov D. LC–MS/MS as a tool for TDM services: where are we?.Clin. Biochem. 2016; 49: 1009-1023Crossref PubMed Scopus (24) Google Scholar].There are also studies focusing on improving MS-based approaches for TDM measurements. One emergent strategy is the replacement of conventional mass analyzer (triple quadrupoles) by Orbitrap technology, allowing high mass resolution measurements over wider concentration ranges [8.Lindner J.M. et al.A semi-automated, isotope-dilution high-resolution mass spectrometry assay for therapeutic drug monitoring of antidepressants.Clin. Mass Spectrom. 2019; 14: 89-98Crossref Scopus (1) Google Scholar]. This high-resolution mass spectrometry approach has been implemented and tested for anticancer drugs [9.Bhatnagar A. et al.Quantitation of the anticancer drug abiraterone and its metabolite Δ(4)-abiraterone in human plasma using high-resolution mass spectrometry.J. Pharm. Biomed. Anal. 2018; 154: 66-74Crossref PubMed Scopus (5) Google Scholar,95.Dahmane E. et al.Quantitative monitoring of tamoxifen in human plasma extended to 40 metabolites using liquid-chromatography high-resolution mass spectrometry: new investigation capabilities for clinical pharmacology.Anal. Bioanal. Chem. 2014; 406: 2627-2640Crossref PubMed Scopus (0) Google Scholar], antivirals [96.Qu L. et al.Quantitative performance of online SPE-LC coupled to Q-Exactive for the analysis of sofosbuvir in human plasma.RSC Adv. 2015; 5: 98269-98277Crossref Google Scholar], antifungals [97.Qu L. et al.Utilizing online-dual-SPE-LC with HRMS for the simultaneous quantification of amphotericin B, fluconazole, and fluorocytosine in human plasma and cerebrospinal fluid.Talanta. 2017; 165: 449-457Crossref PubMed Scopus (8) Google Scholar], antibiotics [98.Lefeuvre S. et al.A simple ultra-high-performance liquid chromatography-high resolution mass spectrometry assay for the simultaneous quantification of 15 antibiotics in plasma.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2017; 1065–1066: 50-58Crossref PubMed Scopus (18) Google Scholar,99.Deltombe O. et al.Development and validation of an ultra-high performance liquid chromatography – high resolution mass spectrometry method for the quantification of total and free teicoplanin in human plasma.Clin. Biochem. 2019; 65: 29-37Crossref PubMed Scopus (3) Google Scholar], and psychoactive drugs [8.Lindner J.M. et al.A semi-automated, isotope-dilution high-resolution mass spectrometry assay for therapeutic drug monitoring of antidepressants.Clin. Mass Spectrom. 2019; 14: 89-98Crossref Scopus (1) Google Scholar]. The basic principle of all chromatographic methods is the separation of unknown components within a mobile phase by hindering the relative mobility of each molecule by interactions between the eluent and the stationary phase. The mobile phase can be a gas, supercritical fluid, organic solvent, or ionic liquid. As the eluents leave the separation column at their respective retention times, compounds are identified using a variety of techniques with different complexities, such as UV/Vis spectrophotometry, refractive index, DAD, FID, and MS. The selection of mobile and stationary phases is the most critical parameter as they determine the success rate of adequate resolution of individual compound peaks. The very first junction in the decision-making process is the choice between GC and LC. Although GC ensures high resolution, it requires the compounds to be gaseous or intrinsically volatile, or have a volatile derivative. Therefore, only about 20% of the organic compounds are separable via GC. Conversely, LC can be used for a wide range of compounds without the need for derivatization, which makes it amenable for at least 80% of the candidate compounds. This is why LC methods such as HPLC are usually the methods of choice in clinical laboratories, except for the few cases where LC is not suitable. The second decision is the type of detector coupled with the chromatography method. A variety of detectors are utilized in different fields, yet LC-MS/MS has been preferred in both reference and clinical laboratories for more than two decades due to its superior specificity and sensitivity over conventional immunoassays, the possibility of processing multiple analytes, and smaller sample volume requirements [6.Decosterd L.A. et al.The emerging role of multiplex tandem mass spectrometry analysis for therapeutic drug monitoring and personalized medicine.Trends Anal. Chem. 2016; 84: 5-13Crossref Scopus (3) Google Scholar,94.Shipkova M. Svinarov D. LC–MS/MS as a tool for TDM services: where are we?.Clin. Biochem. 2016; 49: 1009-1023Crossref PubMed Scopus (24) Google Scholar]. There are also studies focusing on improving MS-based approaches for TDM measurements. One emergent strategy is the replacement of conventional mass analyzer (triple quadrupoles) by Orbitrap technology, allowing high mass resolution measurements over wider concentration ranges [8.Lindner J.M. et al.A semi-automated, isotope-dilution high-resolution mass spectrometry assay for therapeutic drug monitoring of antidepressants.Clin. Mass Spectrom. 2019; 14: 89-98Crossref Scopus (1) Google Scholar]. This high-resolution mass spectrometry approach has been implemented and tested for anticancer drugs [9.Bhatnagar A. et al.Quantitation of the anticancer drug abiraterone and its metabolite Δ(4)-abiraterone in human plasma using high-resolution mass spectrometry.J. Pharm. Biomed. Anal. 2018; 154: 66-74Crossref PubMed Scopus (5) Google Scholar,95.Dahmane E. et al.Quantitative monitoring of tamoxifen in human plasma extended to 40 metabolites using liquid-chromatography high-resolution mass spectrometry: new investigation capabilities for clinical pharmacology.Anal. Bioanal. Chem. 2014; 406: 2627-2640Crossref PubMed Scopus (0) Google Scholar], antivirals [96.Qu L. et al.Quantitative performance of online SPE-LC coupled to Q-Exactive for the analysis of sofosbuvir in human plasma.RSC Adv. 2015; 5: 98269-98277Crossref Google Scholar], antifungals [97.Qu L. et al.Utilizing online-dual-SPE-LC with HRMS for the simultaneous quantification of amphotericin B, fluconazole, and fluorocytosine in human plasma and cerebrospinal fluid.Talanta. 2017; 165: 449-457Crossref PubMed Scopus (8) Google Scholar], antibiotics [98.Lefeuvre S. et al.A simple ultra-high-performance liquid chromatography-high resolution mass spectrometry assay for the simultaneous quantification of 15 antibiotics in plasma.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2017; 1065–1066: 50-58Crossref PubMed Scopus (18) Google Scholar,99.Deltombe O. et al.Development and validation of an ultra-high performance liquid chromatography – high resolution mass spectrometry method for the quantification of total and free teicoplanin in human plasma.Clin. Biochem. 2019; 65: 29-37Crossref PubMed Scopus (3) Google Scholar], and psychoactive drugs [8.Lindner J.M. et al.A semi-automated, isotope-dilution high-resolution mass spectrometry assay for therapeutic drug monitoring of antidepressants.Clin. Mass Spectrom. 2019; 14: 89-98Crossref Scopus (1) Google Scholar]. Accordingly, there has been a significant effort to increase the throughput of chromatographic methods [10.Veringa A. et al.LC-MS/MS for therapeutic drug monitoring of anti-infective drugs.Trends Anal. Chem. 2016; 84: 34-40Crossref Scopus (26) Google Scholar]. Pioneering multiplex approaches have been reported for antiretroviral agents (ARVs) [11.Bollen P.D.J. et al.Development and validation of an UPLC-MS/MS bioanalytical method for simultaneous quantification of the antiretroviral drugs dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine in human plasma.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2019; 1105: 76-84Crossref PubMed Scopus (8) Google Scholar], antifungals [12.Yoon S.J. et al.Experience with therapeutic drug monitoring of three antifungal agents using an LC-MS/MS method in routine clinical practice.Clin. Biochem. 2019; 70: 14-17Crossref PubMed Scopus (0) Google Scholar], antineoplastics [13.van Nuland M. et al.Development and validation of an UPLC-MS/MS method for the therapeutic drug monitoring of oral anti-hormonal drugs in oncology.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2019; 1106–1107: 26-34Crossref PubMed Scopus (6) Google Scholar], antibiotics [6.Decosterd L.A. et al.The emerging role of multiplex tandem mass spectrometry analysis for therapeutic drug monitoring and personalized medicine.Trends Anal. Chem. 2016; 84: 5-13Crossref Scopus (3) Google Scholar,7.Sime F.B. et al.Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2014; 960: 134-144Crossref PubMed Scopus (0) Google Scholar,14.Parker S.L. et al.A validated LC-MSMS method for the simultaneous quantification of meropenem and vaborbactam in human plasma and renal replacement therapy effluent and its application to a pharmacokinetic study.Anal. Bioanal. Chem. 2019; 411: 7831-7840Crossref PubMed Scopus (0) Google Scholar], antidepressants [15.Weber J. et al.Validation of a dried blood spot method for therapeutic drug monitoring of citalopram, mirtazapine and risperidone and its active metabolite 9-hydroxyrisperidone using HPLC–MS.J. Pharm. Biomed. Anal. 2017; 140: 347-354Crossref PubMed Scopus (11) Google Scholar], and immunosuppressive drugs [16.Krnáč D. et al.A new HPLC-MS/MS method for simultaneous determination of cyclosporine A, tacrolimus, sirolimus and everolimus for routine therapeutic drug monitoring.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2019; 1128: 121772Crossref PubMed Scopus (1) Google Scholar] in the past decade. More recently, ultra-performance liquid chromatography (UPLC)-MS/MS has been used for simultaneous quantification of antibiotics [17.Magréault S. et al.UPLC/MS/MS assay for the simultaneous determination of seven antibiotics in human serum–application to pediatric studies.J. Pharm. Biomed. Anal. 2019; 174: 256-262Crossref PubMed Scopus (0) Google Scholar] and ARVs from plasma [11.Bollen P.D.J. et al.Development and validation of an UPLC-MS/MS bioanalytical method for simultaneous quantification of the antiretroviral drugs dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine in human plasma.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2019; 1105: 76-84Crossref PubMed Scopus (8) Google Scholar] and breast milk samples [18.Ramírez-Ramírez A. et al.Simultaneous quantification of four antiretroviral drugs in breast milk samples from HIV-positive women by an ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method.PLoS One. 2018; 13: 1-15Crossref Scopus (3) Google Scholar]. Another focus is the extension of TDM studies toward unconventional samples and sampling. Several LC-MS/MS methods have been developed and applied for hair [11.Bollen P.D.J. et al.Development and validation of an UPLC-MS/MS bioanalytical method for simultaneous quantification of the antiretroviral drugs dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine in human plasma.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2019; 1105: 76-84Crossref PubMed Scopus (8) Google Scholar,18.Ramírez-Ramírez A. et al.Simultaneous quantification of four antiretroviral drugs in breast milk samples from HIV-positive women by an ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method.PLoS One. 2018; 13: 1-15Crossref Scopus (3) Google Scholar], dried blood spots [19.Velghe S. et al.Fully automated therapeutic drug monitoring of anti-epileptic drugs making use of dried blood spots.J. Chromatogr. A. 2019; 1601: 95-103Crossref PubMed Scopus (3) Google Scholar], urine [20.Naicker S. et al.A UHPLC–MS/MS method for the simultaneous determination of piperacillin and tazobactam in plasma (total and unbound), urine and renal replacement therapy effluent.J. Pharm. Biomed. Anal. 2018; 148: 324-333Crossref PubMed Scopus (3) Google Scholar], sweat [21.Xing Y. et al.A new concept of efficient therapeutic drug monitoring using the high-resolution continuum source absorption spectrometry and the surface enhanced Raman spectroscopy.Spectrochim. Acta Part B At. Spectrosc. 2018; 142: 91-96Crossref Scopus (3) Google Scholar], saliva [22.Ventura S. et al.Determination of lamotrigine in human plasma and saliva using microextraction by packed sorbent and high performance liquid chromatography–diode array detection: an innovative bioanalytical tool for therapeutic drug monitoring.Microchem. J. 2017; 130: 221-228Crossref Scopus (12) Google Scholar,23.Ghareeb M. et al.Tacrolimus concentra
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