The Experts below are selected from a list of 300 Experts worldwide ranked by ideXlab platform
Uwe Fuhr - One of the best experts on this subject based on the ideXlab platform.
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A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug–Drug Interactions
Clinical Pharmacokinetics, 2019Co-Authors: Xia Li, Sebastian Frechen, Thorsten Lehr, Max Taubert, Chih‐hsuan Hsin, Gerd Mikus, Pertti J. Neuvonen, Klaus T. Olkkola, Teijo I. Saari, Uwe FuhrAbstract:Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and Time-Dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug–drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore Time-Dependent Inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration–time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim^®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration–time curve (AUC), maximum concentration ( C _max), and trough concentrations for multiple dosings ( C _trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration–time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC_50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate C _max ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate C _max ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1–2 mg/L to
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Development and validation of an in vitro, seven-in-one human cytochrome P450 assay for evaluation of both direct and Time-Dependent Inhibition.
Journal of Pharmacological and Toxicological Methods, 2015Co-Authors: Dominik Dahlinger, Sabrina Duechting, Daniela Nuecken, Konrad Sydow, Uwe Fuhr, Sebastian FrechenAbstract:Abstract Introduction Direct and Time-Dependent Inhibition (TDI) of cytochrome P450 enzymes (CYP) raises drug safety concerns and has major implications in drug development. This study describes the development of a liquid chromatography-tandem mass spectrometry (LC–MS/MS) based screening tool to simultaneously assess both the direct and the Time-Dependent inhibitory potential of xenobiotics on the seven major CYPs using a two-step approach. Methods The in vitro cocktail of FDA recognized model substrates was incubated with human liver microsomes (HLM) and consisted of caffeine (CYP1A2), bupropion (CYP2B6), rosiglitazone (CYP2C8), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A4). Direct and Time-Dependent inhibitory profiles of direct and Time-Dependent reference inhibitors for each CYP were studied. For validation, the results were compared to those obtained with the traditional single substrate approach. Statistical uncertainty was quantified using the bootstrap method. Results The direct Inhibition assay showed an acceptable fold bias of 1.35 (geometric mean fold absolute deviation, range 1.01–2.61) in the IC 50 values for the cocktail assay compared to the single substrate results with no trend for under- or overestimation. Using a single point inactivation assay to assess TDI, we were able to identify all seven tested Time-Dependent reference inhibitors, without any false negatives. Discussion The presented design enhances throughput by assessing the seven major CYPs simultaneously and allows for detection of and discrimination between direct and Time-Dependent CYP Inhibition via IC 50 and single point inactivation experiments. For the latter, a threshold of 10% TDI is proposed for carrying out more detailed inactivation kinetic experiments.
Sean Ekins - One of the best experts on this subject based on the ideXlab platform.
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integrated in silico in vitro strategy for addressing cytochrome p450 3a4 time dependent Inhibition
Chemical Research in Toxicology, 2010Co-Authors: Michael Zientek, Chad L Stoner, Robyn Ayscue, Jacquelyn Klugmcleod, Ying Jiang, Michael A West, Claire Collins, Sean EkinsAbstract:Throughout the past decade, the expectations from the regulatory agencies for safety, drug−drug interactions (DDIs), pharmacokinetic, and disposition characterization of new chemical entities (NCEs) by pharmaceutical companies seeking registration have increased. DDIs are frequently assessed using in silico, in vitro, and in vivo methodologies. However, a key gap in this screening paradigm is a full structural understanding of Time-Dependent Inhibition (TDI) on the cytochrome P450 systems, particularly P450 3A4. To address this, a number of high-throughput in vitro assays have been developed. This work describes an automated assay for TDI using two concentrations at two time points (2 + 2 assay). Data generated with this assay for over 2000 compounds from multiple therapeutic programs were used to generate in silico Bayesian classification models of P450 3A4-mediated TDI. These in silico models were validated using several external test sets and multiple random group testing (receiver operator curve value...
Xia Li - One of the best experts on this subject based on the ideXlab platform.
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A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.
Clinical Pharmacokinectics, 2019Co-Authors: Xia Li, Sebastian Frechen, Thorsten Lehr, Max Taubert, Chih‐hsuan Hsin, Gerd Mikus, Pertti J. Neuvonen, Klaus T. Olkkola, Teijo I. SaariAbstract:Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and Time-Dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug–drug interactions (DDIs) with CYP3A4 substrates in more detail. In vitro assays were carried out to explore Time-Dependent Inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration–time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration–time curve (AUC), maximum concentration (Cmax), and trough concentrations for multiple dosings (Ctrough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration–time datasets over the full range of recommended intravenous and oral dosing regimens. The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate Cmax ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate Cmax ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1–2 mg/L to
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A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug–Drug Interactions
Clinical Pharmacokinetics, 2019Co-Authors: Xia Li, Sebastian Frechen, Thorsten Lehr, Max Taubert, Chih‐hsuan Hsin, Gerd Mikus, Pertti J. Neuvonen, Klaus T. Olkkola, Teijo I. Saari, Uwe FuhrAbstract:Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and Time-Dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug–drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore Time-Dependent Inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration–time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim^®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration–time curve (AUC), maximum concentration ( C _max), and trough concentrations for multiple dosings ( C _trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration–time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC_50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate C _max ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate C _max ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1–2 mg/L to
Sebastian Frechen - One of the best experts on this subject based on the ideXlab platform.
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A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug–Drug Interactions
Clinical Pharmacokinetics, 2019Co-Authors: Xia Li, Sebastian Frechen, Thorsten Lehr, Max Taubert, Chih‐hsuan Hsin, Gerd Mikus, Pertti J. Neuvonen, Klaus T. Olkkola, Teijo I. Saari, Uwe FuhrAbstract:Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and Time-Dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug–drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore Time-Dependent Inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration–time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim^®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration–time curve (AUC), maximum concentration ( C _max), and trough concentrations for multiple dosings ( C _trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration–time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC_50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate C _max ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate C _max ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1–2 mg/L to
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A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.
Clinical Pharmacokinectics, 2019Co-Authors: Xia Li, Sebastian Frechen, Thorsten Lehr, Max Taubert, Chih‐hsuan Hsin, Gerd Mikus, Pertti J. Neuvonen, Klaus T. Olkkola, Teijo I. SaariAbstract:Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and Time-Dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug–drug interactions (DDIs) with CYP3A4 substrates in more detail. In vitro assays were carried out to explore Time-Dependent Inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration–time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration–time curve (AUC), maximum concentration (Cmax), and trough concentrations for multiple dosings (Ctrough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration–time datasets over the full range of recommended intravenous and oral dosing regimens. The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate Cmax ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate Cmax ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1–2 mg/L to
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Development and validation of an in vitro, seven-in-one human cytochrome P450 assay for evaluation of both direct and Time-Dependent Inhibition.
Journal of Pharmacological and Toxicological Methods, 2015Co-Authors: Dominik Dahlinger, Sabrina Duechting, Daniela Nuecken, Konrad Sydow, Uwe Fuhr, Sebastian FrechenAbstract:Abstract Introduction Direct and Time-Dependent Inhibition (TDI) of cytochrome P450 enzymes (CYP) raises drug safety concerns and has major implications in drug development. This study describes the development of a liquid chromatography-tandem mass spectrometry (LC–MS/MS) based screening tool to simultaneously assess both the direct and the Time-Dependent inhibitory potential of xenobiotics on the seven major CYPs using a two-step approach. Methods The in vitro cocktail of FDA recognized model substrates was incubated with human liver microsomes (HLM) and consisted of caffeine (CYP1A2), bupropion (CYP2B6), rosiglitazone (CYP2C8), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A4). Direct and Time-Dependent inhibitory profiles of direct and Time-Dependent reference inhibitors for each CYP were studied. For validation, the results were compared to those obtained with the traditional single substrate approach. Statistical uncertainty was quantified using the bootstrap method. Results The direct Inhibition assay showed an acceptable fold bias of 1.35 (geometric mean fold absolute deviation, range 1.01–2.61) in the IC 50 values for the cocktail assay compared to the single substrate results with no trend for under- or overestimation. Using a single point inactivation assay to assess TDI, we were able to identify all seven tested Time-Dependent reference inhibitors, without any false negatives. Discussion The presented design enhances throughput by assessing the seven major CYPs simultaneously and allows for detection of and discrimination between direct and Time-Dependent CYP Inhibition via IC 50 and single point inactivation experiments. For the latter, a threshold of 10% TDI is proposed for carrying out more detailed inactivation kinetic experiments.
Michael Zientek - One of the best experts on this subject based on the ideXlab platform.
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Use of a Multistaged Time-Dependent Inhibition Assay to Assess the Impact of Intestinal Metabolism on Drug-Drug Interaction Potential
Drug Metabolism and Disposition, 2011Co-Authors: Michael Zientek, Deepak DalvieAbstract:In early discovery, compounds are often eliminated because of their potential to undergo metabolic activation and/or cytochrome P450 Time-Dependent inactivation (TDI). The blockbuster drug raloxifene is an example of a compound that would have been eliminated in the current paradigm. Despite raloxifene9s in vitro bioactivation and TDI of CYP3A4, it is well tolerated in patients with no drug-drug interactions. This discordance is attributed to its presystemic glucuronidation, thereby decreasing the amount of unchanged raloxifene available for CYP3A inactivation. The current study used raloxifene as a model to assess the effect of hepatic and intestinal glucuronidation on the kinetic parameters of CYP3A4 inactivation. Therefore, a simple multistaged Time-Dependent inactivation using UDP-glucuronosyltransferase-enabled and -absent reactions was built to understand the impact of the gut metabolism on inactivation potential. The results of these experiments demonstrated a 2.7-fold change in inactivation efficiency of CYP3A4. Incorporation of these results into a simulated midazolam drug-drug interaction study showed very little change in the pharmacokinetic parameters of the victim drug. In contrast, the absence of glucuronidation resulted in a 4.1-fold increase in the area under the curve (AUC) of midazolam, when in the presence of raloxifene, hence providing an understanding of the impact of intestinal glucuronidation on raloxifene9s Time-Dependent Inhibition of CYP3A4 and also providing a validation of a simple in vitro experiment to assess the influence of gut metabolism on Time-Dependent inhibitors at the discovery phase.
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integrated in silico in vitro strategy for addressing cytochrome p450 3a4 time dependent Inhibition
Chemical Research in Toxicology, 2010Co-Authors: Michael Zientek, Chad L Stoner, Robyn Ayscue, Jacquelyn Klugmcleod, Ying Jiang, Michael A West, Claire Collins, Sean EkinsAbstract:Throughout the past decade, the expectations from the regulatory agencies for safety, drug−drug interactions (DDIs), pharmacokinetic, and disposition characterization of new chemical entities (NCEs) by pharmaceutical companies seeking registration have increased. DDIs are frequently assessed using in silico, in vitro, and in vivo methodologies. However, a key gap in this screening paradigm is a full structural understanding of Time-Dependent Inhibition (TDI) on the cytochrome P450 systems, particularly P450 3A4. To address this, a number of high-throughput in vitro assays have been developed. This work describes an automated assay for TDI using two concentrations at two time points (2 + 2 assay). Data generated with this assay for over 2000 compounds from multiple therapeutic programs were used to generate in silico Bayesian classification models of P450 3A4-mediated TDI. These in silico models were validated using several external test sets and multiple random group testing (receiver operator curve value...
