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Antonio Davolio – One of the best experts on this subject based on the ideXlab platform.

  • uplc ms ms method for the simultaneous quantification of three new Antiretroviral Drugs dolutegravir elvitegravir and rilpivirine and other thirteen Antiretroviral agents plus cobicistat and ritonavir boosters in human plasma
    Journal of Pharmaceutical and Biomedical Analysis, 2017
    Co-Authors: Marco Simiele, Stefano Bonora, Alessandra Ariaudo, Amedeo De Nicolo, Fabio Favata, Martina Ferrante, Chiara Carcieri, Giovanni Di Perri, Antonio Davolio
    Abstract:

    Abstract Rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) are the latest Antiretroviral Drugs approved for treatment of HIV infection. Currently, poor information is currently available concerning their pharmacokinetic and pharmacodynamic properties, thus making the use of therapeutic drugdrug monitoring for these Drugs not useful. This lack of information is partially due to the absence of an high-throughput method for their simultaneous quantification together with other Antiretroviral Drugs. In this work, we describe the development and validation of a new UPLC–MS/MS method to quantify these Drugs, together with other fourteen Antiretroviral agents, in human plasma. One hundred microliters of plasma samples were added with internal standard (6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline), underwent a simple protein precipitation with methanol:acetonitrile (50:50 v/v) followed by sample dilution with water. Chromatographic separation was performed on a Acquity® UPLC HSS T3 column (150 mm x 2.1 mm I.D) with a particle size of 1.8 μm and compounds were detected with a tandem mass detector, monitoring two ion transitions for each Drugs. The mean recovery of RPV, DTG and EVG were 101%, 87% and 112.3% respectively. Accuracy and precision inter/intra-day were below 15% for all Drugs, in accordance to Food and Drug Administration guidelines requirements. The UPLC–MS/MS method reported here could be used routinely to monitor plasma concentrations of antiviral Drugs, including RPV, DTG and EVG.

Peter I Pillans – One of the best experts on this subject based on the ideXlab platform.

  • the current role of liquid chromatography tandem mass spectrometry in therapeutic drug monitoring of immunosuppressant and Antiretroviral Drugs
    Clinical Biochemistry, 2011
    Co-Authors: Paul J Taylor, Chunhui Tai, Michael E Franklin, Peter I Pillans
    Abstract:

    Therapeutic drugdrug monitoring of critical dose immunosuppressant Drugs is established clinical practice and there are similar good reasons to monitor Antiretrovirals. The aim of this article is to review the recent literature (last five years), with particular reference to the use of liquid chrochromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS offers many potential advantages. The superior selectivity of LC-MS/MS over immunoassays for immunosuppressant Drugs has been widely reported. Simultaneous measurement of a number of Drugs can be performed. It is currently routine practice for the four major immunosuppressants (cyclosporin, tacrolimus, sirolimus and everolimus) to be simultaneously measured in whole blood. While up to 17 Antiretroviral Drugs have been simultaneously measured in plasma. The exquisite sensitivity of LC-MS/MS also provides the opportunity to measure these Drugs in alternative matrices, such as dried blood spots, saliva, peripheral blood mononuclear cells and tissue. However, the clinical utility of measuring these classes of Drugs in alternative matrices is still to be determined.

Stefano Bonora – One of the best experts on this subject based on the ideXlab platform.

  • A review of the potential mechanisms of neuronal toxicity associated with Antiretroviral Drugs
    Journal of NeuroVirology, 2020
    Co-Authors: Ilaria De Benedetto, Mattia Trunfio, Giulia Guastamacchia, Stefano Bonora, Andrea Calcagno
    Abstract:

    Highly active Antiretroviral treatment has led to unprecedented efficacy and tolerability in people living with HIV. This effect was also observed in the central nervous system with the nowadays uncommon observation of dementias; yet in more recent works milder forms are still reported in 20–30% of optimally treated individuals. The idea of a subclinical neuronal toxicity induced by Antiretrovirals has been proposed and was somehow supported by the late-emerging effects associated with efavirenz use. In this manuscript we are reviewing all the potential mechanisms by which Antiretroviral Drugs have been associated with in vitro, ex vivo, or in vivo toxicity to cells pertaining to the central nervous system (neurons, astrocytes, oligodendrocytes, and endothelial cells). These include direct or indirect effects and pathological pathways such as amyloid deposition, damage to small cerebral vessels, and impairment in neurotransmission. The aim of this review is therefore to provide a detailed description of the available literature in order to guide further clinical research for improving patients’ neurocognition and quality of life.

  • uplc ms ms method for the simultaneous quantification of three new Antiretroviral Drugs dolutegravir elvitegravir and rilpivirine and other thirteen Antiretroviral agents plus cobicistat and ritonavir boosters in human plasma
    Journal of Pharmaceutical and Biomedical Analysis, 2017
    Co-Authors: Marco Simiele, Stefano Bonora, Alessandra Ariaudo, Amedeo De Nicolo, Fabio Favata, Martina Ferrante, Chiara Carcieri, Giovanni Di Perri, Antonio Davolio
    Abstract:

    Abstract Rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) are the latest Antiretroviral Drugs approved for treatment of HIV infection. Currently, poor information is currently available concerning their pharmacokinetic and pharmacodynamic properties, thus making the use of therapeutic drug monitoring for these Drugs not useful. This lack of information is partially due to the absence of an high-throughput method for their simultaneous quantification together with other Antiretroviral Drugs. In this work, we describe the development and validation of a new UPLC–MS/MS method to quantify these Drugs, together with other fourteen Antiretroviral agents, in human plasma. One hundred microliters of plasma samples were added with internal standard (6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline), underwent a simple protein precipitation with methanol:acetonitrile (50:50 v/v) followed by sample dilution with water. Chromatographic separation was performed on a Acquity® UPLC HSS T3 column (150 mm x 2.1 mm I.D) with a particle size of 1.8 μm and compounds were detected with a tandem mass detector, monitoring two ion transitions for each Drugs. The mean recovery of RPV, DTG and EVG were 101%, 87% and 112.3% respectively. Accuracy and precision inter/intra-day were below 15% for all Drugs, in accordance to Food and Drug Administration guidelines requirements. The UPLC–MS/MS method reported here could be used routinely to monitor plasma concentrations of antiviral Drugs, including RPV, DTG and EVG.

D M Burger – One of the best experts on this subject based on the ideXlab platform.

  • 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
    Journal of Chromatography B, 2019
    Co-Authors: Pauline D.j. Bollen, Marga J A De Graaffteulen, Stein Schalkwijk, D M Burger
    Abstract:

    Abstract Dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine are Antiretroviral Drugs used as part of combined Antiretroviral treatment for HIV-infection. For quantification of these Drugs in human K2EDTA plasma samples an ultra-high performance liquid chrochromatography-tandem mass spectrometry (UPLC-MS/MS) bioanalytical method was developed and validated. Stable isotope labeled internal standards were used for each analyte. Simple protein precipitation with methanol was implemented to prepare plasma samples of at least 50 μL. The method was validated for dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine over the ranges 9.7–9700, 52–10,470, 9.7–9730, 73–14,680 and 15–3010 ng/mL, respectively. Within-run and between-run accuracy and precision were within ±15% of the nominal concentration for quality controls at high, medium and low concentrations, and within ±20% at the lower limit of quantification for all analytes. Recovery was ≥76% and reproducible. Long-term stability of patient plasma samples was demonstrated for at least 12 months at −40 °C (4 months for etravirine). Currently, this robust method with a run time of 10 min is used in clinical research and for therapeutic drugdrug monitoring of these frequently used Antiretroviral Drugs.

David M. Burger – One of the best experts on this subject based on the ideXlab platform.

  • The role of formulation on the pharmacokinetics of Antiretroviral Drugs.
    Expert opinion on drug metabolism & toxicology, 2014
    Co-Authors: Diane E. T. Bastiaans, Tim R. Cressey, Herman Vromans, David M. Burger
    Abstract:

    Introduction: A multitude of Antiretroviral drug formulations are now available for HIV-infected adults and children. These formulations include individual and co-formulated Drugs, many of which are also supplied in generic versions. Many Antiretroviral Drugs have a low aqueous solubility and poor bioavailability. Drug formulation can significantly affect bioavailability, and given the increasing number of new formulations and drug combinations, it is important to be aware that formulation can influence the pharmacokinetics of Antiretroviral Drugs.Areas covered: This review provides an overview of studies assessing the pharmacokinetics of different Antiretroviral drug formulations in adults and children, including fixed-dose combinations. For some Antiretroviral Drugs, differences in pharmacokinetics have been described, with largest differences in exposure when a liquid formulation is compared to a tablet or capsule formulation. Biopharmaceutical properties of Antiretroviral Drugs relevant to bioavailabi…

  • the international interlaboratory quality control program for measurement of Antiretroviral Drugs in plasma a global proficiency testing program
    Therapeutic Drug Monitoring, 2011
    Co-Authors: David M. Burger, Marga Teulen, Jaco Eerland, Anneke R Harteveld, Rob E Aarnoutse, Daan J Touw
    Abstract:

    The International Interlaboratory Quality Control Program for Measurement of Antiretroviral Drugs in Plasma was initiated in 1999 by Radboud University Nijmegen Medical Center, The Netherlands, and continued later on in collaboration with the Dutch Association for Quality Assessment in Therapeutic DrugDrug Monitoring and Clinical Toxicology (www.kkgt.nl). The aim of this analysis was to evaluate the first 10 years of the Program and to determine variables associated with reporting of less accurate results. Two rounds are organized annually in which blind samples are shipped to participants containing a low, medium, or high concentration of each Antiretroviral drug. Any reported result that deviates more than 20% from the spiked concentration is defined as inaccurate. By the end of 2009, the number of laboratories participating in the Program had increased to 56; 44 (79%) are located in Europe. A total of 12,798 test results was available for analysis, of which 2104 (16.4%) were reported as inaccurate. Performance was best for samples containing nevirapine (mean of inadequate scores per round: 11.1%) and lopinavir (11.9%) and worst for indinavir (18.7%), atazanavir (18.9%), saquinavir (19.6%), and nelfinavir (21.3%). High and medium concentrations were less frequently reported as inaccurate than low concentrations: 13.5%, 13.0%, and 22.4%, respectively. Although the overall performance of the laboratories varied per year, a trend was visible for improvement over time with 19.9% of the results being inaccurate in 2002 (n = 20 laboratories) to 15.7% in 2009 (n = 56 laboratories). The Program provides a proficiency testing program in which laboratories are alerted to potential analytical errors while performing therapeutic drugdrug monitoring in HIV-infected patients. Laboratories should put more effort in adequately analyzing concentrations of Antiretroviral Drugs with low minimum effective concentrations.

  • therapeutic drug monitoring an aid to optimising response to Antiretroviral Drugs
    Drugs, 2003
    Co-Authors: Rob E Aarnoutse, Jonathan M Schapiro, Charles A Boucher, Y A Hekster, David M. Burger
    Abstract:

    Therapeutic drugdrug monitoring (TDM) has been proposed as a means to optimise response to highly active Antiretroviral therapy (HAART) in HIV infection. Protease inhibitors (PIs) and the non-nucleoside reverse trantranscriptase inhibitors (NNRTIs) efavirenz and nevirapine satisfy many criteria for TDM. Nucleoside reverse trantranscriptase inhibitors (NRTIs) are not suitable candidates for TDM, since no clear plasma concentration-effect relationships have been established for these Drugs.Several important limitations to the application of TDM for Antiretroviral Drugs should be recognised, including uncertainty about the best pharmacokinetic predictor of response and insufficient validation of target concentrations for individual PIs and NNRTIs. Data from two clinical trials support the use of TDM in treatment-naive HIV-infected patients who start with an indinavir- or nelfinavir-based regimen. TDM either prevented virological failures (presumably by preventing the development of resistance) or treatment discontinuations due to concentration-related toxicity. Application of routine TDM in other patient groups (treatment-experienced patients) or for Drugs other than indinavir or nelfinavir (NNRTIs, other PIs, combination of PIs) is speculative at this moment. However, TDM can be used in selected patient groups (children, pregnant women, patients with renal or hepatic dysfunction) to confirm adequate drug concentrations, and for management of drug-drug interactions.TDM in treatment-experienced patients may be optimally used in conjunction with resistance testing. The integration of pharmacological and virological measures in the inhibitory quotient (IQ) needs to be standardised and elaborated further. TDM should be accompanied by careful assessment of adherence and can itself help identify non-adherence, although a drug concentration only reflects the last few drug doses taken by a patient. Additional clinical trials are needed before routine TDM can be adopted as standard of care in the treatment of HIV infection.