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Cornelis A.m. Van Gestel - One of the best experts on this subject based on the ideXlab platform.
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Toxicokinetics and Toxicodynamics of lead in the soil invertebrate Enchytraeus crypticus
Environmental pollution (Barking Essex : 1987), 2017Co-Authors: Lulu Zhang, Cornelis A.m. Van GestelAbstract:The aim of the present study was to link Pb toxicokinetics to Toxicodynamics in Enchytraeus crypticus. The enchytraeids were exposed for 14 d to different Pb concentrations (uptake phase) in natural Lufa 2.2 soil, followed by a 14-d elimination phase in clean soil. Pb accumulation and enchytraeid mortality were determined at different time intervals. At each exposure concentration, internal Pb concentration increased with exposure time and achieved equilibrium in approximately 7 d. Median lethal concentration (LC50) based on total Pb concentration in soil decreased with exposure time, but did not reach a steady-state level. Pb toxicity, therefore, showed a delay compared to accumulation in E. crypticus. LC50s based on internal Pb concentrations in the surviving animals did reach steady state in approx.14 d, suggesting that linking toxicokinetics to Toxicodynamics may reduce the effects of time. This study highlighted that exposure time, as an important factor in metal uptake and toxicity, should be taken into account in ecotoxicological tests for risk assessment.
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Toxicokinetics and Toxicodynamics of differently coated silver nanoparticles and silver nitrate in Enchytraeus crypticus upon aqueous exposure in an inert sand medium
Environmental toxicology and chemistry, 2015Co-Authors: Emel Topuz, Cornelis A.m. Van GestelAbstract:The aim of the present study was to evaluate the effect of silver nanoparticles (AgNPs) on Enchytraeus crypticus, applying a combined toxicokinetics and Toxicodynamics approach to understand the relationship between survival and the development of internal Ag concentrations in the animals over time. Toxicity tests were conducted in medium composed of well-defined aqueous solutions added to inert quartz sand to avoid the complexity of soil conditions. Citrate-coated AgNPs (AgNP-Cit) and polyvinylpyrrolidone-coated AgNPs (AgNP-PVP) were tested and compared with silver nitrate (AgNO3), which was used as a positive control for Ag ion effects. The median lethal concentration (LC50) values based on Ag concentrations in the solution phase of the test medium decreased over time and reached steady state after 7 d, with AgNO3 and AgNP-PVP being more toxic than AgNP-Cit. Slow dissolution may explain the low uptake kinetics and lower toxicity of AgNP-Cit compared with the other 2 Ag forms. The LC50 values based on internal Ag concentrations in the animals were almost stable over time, highlighting the importance of integrating toxicokinetics and Toxicodynamics and relating survival with internal Ag concentrations. Neither survival-based elimination rates nor internal LC50s in the organisms showed any significant evidence of nano-specific effects for both AgNPs, although they suggested some uptake of particulate Ag for AgNP-Cit. The authors conclude that the toxicity of both types of AgNP probably is mainly attributable to the release of Ag ions. Environ Toxicol Chem 2015;34:2816–2823. © 2015 SETAC
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A combined toxicokinetics and Toxicodynamics approach to assess the effect of porewater composition on cadmium bioavailability to Folsomia candida
Environmental toxicology and chemistry, 2014Co-Authors: Masoud M. Ardestani, Fedor Oduber, Cornelis A.m. Van GestelAbstract:The aim of the present study was to improve our understanding of cadmium bioavailability by linking toxicokinetics and Toxicodynamics. The springtail Folsomia candida was exposed to different cadmium concentrations in solutions embedded in inert quartz sand. Survival and cadmium uptake in the animals were followed for 21 d. After 10 d, some animals were transferred to clean medium to assess cadmium elimination. Using a first-order one-compartment model, an overall uptake rate constant (k1) of 0.18 L kganimal–1 d−1 and an elimination rate constant (k2-TK) of 0.02 d−1 were calculated. Survival decreased with time, resulting in an estimated final median lethal concentration (LC50) of 0.51 mM. A lethal body concentration (LBC) of 4.6 µmol Cd g−1 dry body weight was estimated by multiplying the final LC50 by the bioconcentration factor (k1/k2-TK). The LC50animal values based on internal cadmium concentrations were between 3.56 µmol Cd g−1 and 9.91 µmol Cd g−1 dry body weight, with an overall value of 7.9 µmol Cd g−1 dry body weight (95% confidence interval [CI]: 3.8–12.0 µmol Cd g−1 dry body wt). Because the 95% CI of the LC50animal included the LBC, there was good agreement of cadmium toxicokinetics and Toxicodynamics. Environ Toxicol Chem 2014;33:1570–1577. © 2014 SETAC
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Toxicodynamics of copper and cadmium in Folsomia candida exposed to simulated soil solutions.
Environmental toxicology and chemistry, 2013Co-Authors: Masoud M. Ardestani, Cornelis A.m. Van GestelAbstract:To improve our understanding of metal bioavailability to soil-living invertebrates, the effect of porewater composition on the Toxicodynamics of copper and cadmium in Folsomia candida (Collembola) was investigated. Assuming that porewater is the main exposure route, F. candida was exposed to simulated soil solutions of different composition. Toxicity of copper was slightly lower in a calcium-only solution than in a multication solution. With increasing copper concentrations from 0.005 mM to 1.37 mM, internal copper concentrations similarly increased in both exposure solutions, suggesting that a single cation nutrient solution is suitable for testing F. candida. In the second experiment, animals were exposed for 7 d to copper and cadmium in simplified soil solutions with different calcium (0.2 mM, 0.8 mM, 3.2 mM, 12.8 mM) and pH (5.0, 6.0, 7.0) levels. The median lethal concentration (LC50) values decreased with time in both the calcium and pH series. A hormetic-type effect was observed for copper in the second test, as well as in the calcium-only solution in the first experiment. Because of stronger hormesis, LC50s for copper were higher at lower calcium concentrations. For cadmium, LC50 values were higher at higher calcium concentrations, suggesting competition of calcium with the free cadmium ion. Toxicity of cadmium increased with decreasing pH, while copper was more toxic at intermediate pH. The results show that a Toxicodynamics approach can help to improve the interpretation of metal toxicity to soil invertebrates, taking into account soil solution properties. Environ Toxicol Chem 2013;32:2746–2754. © 2013 SETAC
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Toxicokinetics and Toxicodynamics of nickel in Enchytraeus crypticus.
Environmental toxicology and chemistry, 2013Co-Authors: Cornelis A.m. Van GestelAbstract:Metal toxicity is usually determined at a fixed time point, which may bias the assessment of risks associated with varied exposure time. Time-dependent accumulation and toxicity of nickel in the potworm Enchytraeus crypticus were investigated in solutions embedded in an inert quartz sand matrix. Internal Ni concentration and mortality were determined at 7 different time intervals and interpreted from the perspective of toxicokinetics and Toxicodynamics. A 1-compartment model was used to describe the uptake and elimination kinetics of Ni. At each exposure concentration, Ni concentration in the organisms increased with increasing exposure time, reaching equilibrium after approximately 14 d. Median lethal concentration (LC50) decreased with time and reached an ultimate value of 0.182 mg/L.TheLC50valuesexpressedasinternalNiconcentrations(LC50inter)werealmostconstant(16.7 mg/kgbodydrywt)ateach exposure time. The LC50inter was independent of exposure time, suggesting that internal concentration was a better indicator of Ni toxicity than external concentration. The uptake rate constant was 11.9 L/kg/d, and elimination rate constants were 0.325/d (based on internal concentration) and 0.070/d (based on survival), indicating that not all internal Ni contributes to toxicity. The present study highlights the importance of taking time into account in future toxicity testing and risk assessment practices. Environ Toxicol Chem 2013;32:1835-1841. # 2013 SETAC
Beate Escher - One of the best experts on this subject based on the ideXlab platform.
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toxicokinetic and toxicodynamic model for diazinon toxicity mechanistic explanation of differences in the sensitivity of daphnia magna and gammarus pulex
Environmental Toxicology and Chemistry, 2012Co-Authors: Roman Ashauer, Andreas Kretschmann, Juliane Hollender, Beate EscherAbstract:A mechanistic toxicokinetic and toxicodynamic model for acute toxic effects (immobilization, mortality) of the organothiophosphate insecticide diazinon in Daphnia magna is presented. The model was parameterized using measured external and internal (whole-body) concentrations of diazinon, its toxic metabolite diazoxon, and the inactive metabolite 2-isopropyl-6-methyl-4-pyrimidinol, plus acetylcholinesterase (AChE) activity measured during exposure to diazinon in vivo. The toxicokinetic and toxicodynamic model provides a coherent picture from exposure to the resulting toxic effect on an organism level through internally formed metabolites and the effect on a molecular scale. A very fast reaction of diazoxon with AChE (pseudo first-order inhibition rate constant ki?=?3.3?h-1) compared with a slow formation of diazoxon (activation rate constant kact?=?0.014?h-1) was responsible for the high sensitivity of D. magna toward diazinon. Recovery of AChE activity from inhibition was slow and rate-determining (99% recovery within 16 d), compared with a fast elimination of diazinon (99% elimination within 17?h). The obtained model parameters were compared with toxicokinetic and toxicodynamic parameters of Gammarus pulex exposed to diazinon from previous work. This comparison revealed that G. pulex is less sensitive because of a six times faster detoxification of diazinon and diazoxon and an approximately 400 times lower rate for damage accrual. These differences overcompensate the two times faster activation of diazinon to diazoxon in G. pulex compared to D. magna. The present study substantiates theoretical considerations that mechanistically based effect models are helpful to explain sensitivity differences among different aquatic invertebrates. Environ. Toxicol. Chem. 2012; 31: 20142022. (c) 2012 SETAC
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Toxicokinetic and toxicodynamic model for diazinon toxicity—mechanistic explanation of differences in the sensitivity of Daphnia magna and Gammarus pulex
Environmental toxicology and chemistry, 2012Co-Authors: Andreas Kretschmann, Roman Ashauer, Juliane Hollender, Beate EscherAbstract:A mechanistic toxicokinetic and toxicodynamic model for acute toxic effects (immobilization, mortality) of the organothiophosphate insecticide diazinon in Daphnia magna is presented. The model was parameterized using measured external and internal (whole-body) concentrations of diazinon, its toxic metabolite diazoxon, and the inactive metabolite 2-isopropyl-6-methyl-4-pyrimidinol, plus acetylcholinesterase (AChE) activity measured during exposure to diazinon in vivo. The toxicokinetic and toxicodynamic model provides a coherent picture from exposure to the resulting toxic effect on an organism level through internally formed metabolites and the effect on a molecular scale. A very fast reaction of diazoxon with AChE (pseudo first-order inhibition rate constant ki?=?3.3?h-1) compared with a slow formation of diazoxon (activation rate constant kact?=?0.014?h-1) was responsible for the high sensitivity of D. magna toward diazinon. Recovery of AChE activity from inhibition was slow and rate-determining (99% recovery within 16 d), compared with a fast elimination of diazinon (99% elimination within 17?h). The obtained model parameters were compared with toxicokinetic and toxicodynamic parameters of Gammarus pulex exposed to diazinon from previous work. This comparison revealed that G. pulex is less sensitive because of a six times faster detoxification of diazinon and diazoxon and an approximately 400 times lower rate for damage accrual. These differences overcompensate the two times faster activation of diazinon to diazoxon in G. pulex compared to D. magna. The present study substantiates theoretical considerations that mechanistically based effect models are helpful to explain sensitivity differences among different aquatic invertebrates. Environ. Toxicol. Chem. 2012; 31: 20142022. (c) 2012 SETAC
Thomas G Preuss - One of the best experts on this subject based on the ideXlab platform.
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Disentangling Mechanisms Behind Chronic Lethality through Toxicokinetic-Toxicodynamic Modelling.
Environmental toxicology and chemistry, 2021Co-Authors: André Gergs, Jutta Hager, Eric Bruns, Thomas G PreussAbstract:Ecotoxicological profiles of the three insecticides imidacloprid, thiacloprid and flupyradifurone in terms of acute and chronic effects were analyzed in Chironomus riparius. Toxicokinetic-toxicodynamic modelling revealed that chironomids would die from starvation due to prolonged feeding inhibition under chronic exposures. The starvation effect is an indirect cause for mortality, which, for the neonicotinoids, adds to the direct/acute mortality, while the results suggests that this additional effect is not relevant for flupyradifurone. This article is protected by copyright. All rights reserved.
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demographic toxicokinetic toxicodynamic modeling of lethal effects
Environmental Science & Technology, 2016Co-Authors: André Gergs, Faten Gabsi, Armin Zenker, Thomas G PreussAbstract:The aquatic effect assessment of chemicals is largely based on standardized measures of toxicity determined in short-term laboratory tests which are designed to reduce variability. For this purpose, uniform individuals of a species are kept under environmental and chemical exposure conditions which are as constant as possible. In nature, exposure often appears to be pulsed, effects might last longer than a few days, sensitivity might vary among different sized organisms and populations are usually size or age structured and are subject to demographic processes. To overcome this discrepancy, we tested toxicokinetic–toxicodynamic models of different complexities, including body size scaling approaches, for their ability to represent lethal effects observed for Daphnia magna exposed to triphenyltin. The consequences of the different toxicokinetic and toxicodynamic assumptions for population level responses to pulsed exposure are tested by means of an individual based model and are evaluated by confronting mo...
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Demographic Toxicokinetic–Toxicodynamic Modeling of Lethal Effects
Environmental science & technology, 2016Co-Authors: André Gergs, Faten Gabsi, Armin Zenker, Thomas G PreussAbstract:The aquatic effect assessment of chemicals is largely based on standardized measures of toxicity determined in short-term laboratory tests which are designed to reduce variability. For this purpose, uniform individuals of a species are kept under environmental and chemical exposure conditions which are as constant as possible. In nature, exposure often appears to be pulsed, effects might last longer than a few days, sensitivity might vary among different sized organisms and populations are usually size or age structured and are subject to demographic processes. To overcome this discrepancy, we tested toxicokinetic–toxicodynamic models of different complexities, including body size scaling approaches, for their ability to represent lethal effects observed for Daphnia magna exposed to triphenyltin. The consequences of the different toxicokinetic and toxicodynamic assumptions for population level responses to pulsed exposure are tested by means of an individual based model and are evaluated by confronting mo...
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a toxicokinetic and toxicodynamic modeling approach using myriophyllum spicatum to predict effects caused by short term exposure to a sulfonylurea
Environmental Toxicology and Chemistry, 2016Co-Authors: Simon Heine, Frederik Schild, Walter Schmitt, Ralph Krebber, Gerhard Gorlitz, Thomas G PreussAbstract:Toxicokinetic and toxicodynamic models are a promising tool to address the effects of time-variable chemical exposure. While standard toxicity tests rely, in most cases, on static concentrations, these chemical exposure patterns are unlikely to appear in the field, where time-variable exposure of chemicals is typical. In this study, we integrated toxicodynamic processes into an existing model that includes toxicokinetics and growth of the aquatic plant Myriophyllum spicatum, to predict the impact on plant growth of two iofensulfuron short-term exposure patterns. To establish a method that can be used with standard data from risk assessments, Toxicodynamics of iofensulfuron are based on effect data from a 14-day standard toxicity test using static concentrations. Modelling showed that the toxicokinetic and toxicodynamic growth model of M. spicatum can be successfully used to predict effects of short-term iofensulfuron exposure by using effect data from a standard toxicity test. A general approach is presented, in which time-variable chemical exposures can be evaluated more realistically without conducting additional toxicity studies. This article is protected by copyright. All rights reserved
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Demographic Toxicokinetic–Toxicodynamic Modeling of Lethal Effects
2016Co-Authors: André Gergs, Faten Gabsi, Armin Zenker, Thomas G PreussAbstract:The aquatic effect assessment of chemicals is largely based on standardized measures of toxicity determined in short-term laboratory tests which are designed to reduce variability. For this purpose, uniform individuals of a species are kept under environmental and chemical exposure conditions which are as constant as possible. In nature, exposure often appears to be pulsed, effects might last longer than a few days, sensitivity might vary among different sized organisms and populations are usually size or age structured and are subject to demographic processes. To overcome this discrepancy, we tested toxicokinetic–toxicodynamic models of different complexities, including body size scaling approaches, for their ability to represent lethal effects observed for Daphnia magna exposed to triphenyltin. The consequences of the different toxicokinetic and toxicodynamic assumptions for population level responses to pulsed exposure are tested by means of an individual based model and are evaluated by confronting model predictions with population data for various pulsed exposure scenarios. We provide an example where increased model complexity reduces the uncertainty in model outputs. Furthermore, our results emphasize the importance of considering population demography in toxicokinetics and Toxicodynamics for understanding and predicting potential chemical impacts at higher levels of biological organization
Jason A. Roberts - One of the best experts on this subject based on the ideXlab platform.
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A Systematic Review of the Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Ganciclovir/Valganciclovir in Allogeneic Haematopoietic Stem Cell Transplant Patients
Clinical Pharmacokinetics, 2021Co-Authors: Philip Roland Selby, Sepehr Shakib, Sandra L. Peake, Morgyn S. Warner, David Yeung, Uwe Hahn, Jason A. RobertsAbstract:Background Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients. Objective The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population. Methods We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and Toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included. Results A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and Toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified. Conclusion Further studies of the pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.
Philip Roland Selby - One of the best experts on this subject based on the ideXlab platform.
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A Systematic Review of the Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Ganciclovir/Valganciclovir in Allogeneic Haematopoietic Stem Cell Transplant Patients
Clinical Pharmacokinetics, 2021Co-Authors: Philip Roland Selby, Sepehr Shakib, Sandra L. Peake, Morgyn S. Warner, David Yeung, Uwe Hahn, Jason A. RobertsAbstract:Background Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients. Objective The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population. Methods We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and Toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included. Results A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and Toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified. Conclusion Further studies of the pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.
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a systematic review of the clinical pharmacokinetics pharmacodynamics and Toxicodynamics of ganciclovir valganciclovir in allogeneic haematopoietic stem cell transplant patients
Clinical Pharmacokinectics, 2021Co-Authors: Philip Roland Selby, Sepehr Shakib, Sandra L. Peake, Morgyn S. Warner, Uwe Hahn, David T YeungAbstract:BACKGROUND Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients. OBJECTIVE The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population. METHODS We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and Toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included. RESULTS A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and Toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified. CONCLUSION Further studies of the pharmacokinetics, pharmacodynamics and Toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.
