The Experts below are selected from a list of 31512 Experts worldwide ranked by ideXlab platform
Thorsten Lehr - One of the best experts on this subject based on the ideXlab platform.
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Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists
Pharmaceutical Research, 2019Co-Authors: Anke-katrin Volz, Jasper Dingemanse, Andreas Krause, Thorsten LehrAbstract:Purpose Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) Pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. Methods PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects Modeling approach. Results Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. Conclusion The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.
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Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists.
Pharmaceutical Research, 2019Co-Authors: Anke-katrin Volz, Jasper Dingemanse, Andreas Krause, Thorsten LehrAbstract:Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) Pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects Modeling approach. Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.
Hiroshi Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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Human plasma concentration-time profiles of troglitazone and troglitazone sulfate simulated by in vivo experiments with chimeric mice with humanized livers and semi-physiological Pharmacokinetic Modeling.
Drug metabolism and pharmacokinetics, 2020Co-Authors: Satoshi Ito, Hidetaka Kamimura, Yousuke Yamamoto, Hiroyuki Chijiwa, Takeshi Okuzono, Hiroshi Suemizu, Hiroshi YamazakiAbstract:Abstract Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extra-hepatic elimination of these compounds was negligible. These values were plotted against the replacement indices, and postulated values for virtual 100% chimeric mice were assumed to be equivalent to those in humans. Metabolic formation ratio was estimated by comparing AUCs of troglitazone sulfate after separate administration of troglitazone and troglitazone sulfate. Liver to plasma concentration ratios were obtained from direct measurement. These parameters were extrapolated to 100% chimeric mice and subjected to semi-physiological Pharmacokinetic Modeling using Pharmacokinetic parameters for oral administration taken from literature. Our simulated plasma concentration-time profile of troglitazone agreed well with observed values obtained in clinical study. However, the profile of troglitazone sulfate was far below the reported values. Although the possible reasons for this discrepancy remains unsolved, the combination of chimeric mice with semi-physiological PK Modeling proved to be a useful tool in understanding the function of each PK parameter in human Pharmacokinetics of troglitazone and its conjugated metabolite.
Rahul S. Yerrabelli - One of the best experts on this subject based on the ideXlab platform.
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IntraOmmaya compartmental radioimmunotherapy using ^131I-omburtamab—Pharmacokinetic Modeling to optimize therapeutic index
European Journal of Nuclear Medicine and Molecular Imaging, 2020Co-Authors: Rahul S. Yerrabelli, Edward K. Fung, Kim Kramer, Pat B. Zanzonico, John L. Humm, Hongfen Guo, Neeta Pandit-taskar, Steven M. Larson, Nai-kong V. CheungAbstract:Purpose Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody ^131I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply Pharmacokinetic Modeling to intraOmmaya ^131I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. Methods Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of ^131I-omburtamab for leptomeningeal malignancy. A two-compartment Pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [C_IAR(t)], (b) the AUC of the unbound “harmful” antibody, AUC [C_IA(t)], and (c) the therapeutic index, AUC [C_IAR(t)] ÷ AUC [C_IA(t)]. Results The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of ^131I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [C_IA(t)]) was predicted to increase more quickly than AUC [C_IAR(t)] as a function of ^131I-omburtamab dose, but the balance of therapeutic index and AUC [C_IAR(t)] remained favorable over a broad range of administered doses (0.48–1.40 mg or 881–2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%. Conclusion The 2-compartmental Pharmacokinetic model when applied to intraOmmaya ^131I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. Clinical trial registration ClinicalTrials.gov , NCT00089245.
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intraommaya compartmental radioimmunotherapy using 131 i omburtamab Pharmacokinetic Modeling to optimize therapeutic index
European Journal of Nuclear Medicine and Molecular Imaging, 2020Co-Authors: Rahul S. Yerrabelli, Edward K. Fung, Kim Kramer, Pat B. Zanzonico, John L. Humm, Hongfen Guo, Neeta Pandittaskar, Steven M. LarsonAbstract:Purpose Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody 131I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply Pharmacokinetic Modeling to intraOmmaya 131I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. Methods Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of 131I-omburtamab for leptomeningeal malignancy. A two-compartment Pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [CIAR(t)], (b) the AUC of the unbound "harmful" antibody, AUC [CIA(t)], and (c) the therapeutic index, AUC [CIAR(t)] ÷ AUC [CIA(t)]. Results The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of 131I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [CIA(t)]) was predicted to increase more quickly than AUC [CIAR(t)] as a function of 131I-omburtamab dose, but the balance of therapeutic index and AUC [CIAR(t)] remained favorable over a broad range of administered doses (0.48-1.40 mg or 881-2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%. Conclusion The 2-compartmental Pharmacokinetic model when applied to intraOmmaya 131I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. Clinical trial registration ClinicalTrials.gov , NCT00089245.
Ene I Ette - One of the best experts on this subject based on the ideXlab platform.
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model appropriateness and population Pharmacokinetic Modeling
The Journal of Clinical Pharmacology, 2003Co-Authors: Ene I Ette, Paul J Williams, James R Lane, Edmund V CapparelliAbstract:The purpose of this study was to define model appropriateness, identifying the individual elements thereof, and to set out a framework within which model appropriateness could be determined for population Pharmacokinetic (PPK) models. Model appropriateness was defined by stating the problem to be solved, with the intended use of the model being the pivotal event. The elements of model appropriateness were identified with the type of model (descriptive vs. predictive) determining which elements of model appropriateness need to be executed. An example is presented to show how model appropriateness is determined for the optimal application of PPK models. It was determined that PPK models are developed to solve problems. Model appropriateness depends on identifying the problem, as well as stating the intended use of the model, and requires evaluation of the model for goodness of fit, reliability, and stability if intended for descriptive purposes; for predictive models, validation would be an additional requirement. Descriptive models are used to explain variability in the Pharmacokinetics (PK) of a drug, while predictive models are developed to extrapolate beyond the immediate study population. For those models used for predictive purposes, strong assumptions are made about the relationship to the underlying population from which the data were collected. As an example of determining model appropriateness, a PPK model for 5-fluorocytosine was developed, using NONMEM, version IV. The model was evaluated and validated by the process of percentile bootstrapping. From the PPK model, the range of expected serum concentrations based on two widely used dosing methods (Sanford and the University of California at San Diego [UCSD]) was simulated (Pharsight Trial Designer software). These results indicated that the UCSD method performed well and has the advantage of recommending convenient dosing intervals. In conclusion, considering and applying the principles of model appropriateness to PPK models will result in models that can be applied for their intended use with confidence. Model appropriateness was efficiently established and determined to address the problem of comparing competing dosing strategies.
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Population Pharmacokinetic Modeling: The Importance of Informative Graphics
Pharmaceutical Research, 1995Co-Authors: Ene I Ette, Thomas M. LuddenAbstract:Purpose. The usefulness of several modelling methods were examined in the development of a population Pharmacokinetics model for cefepime.
Anke-katrin Volz - One of the best experts on this subject based on the ideXlab platform.
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Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists
Pharmaceutical Research, 2019Co-Authors: Anke-katrin Volz, Jasper Dingemanse, Andreas Krause, Thorsten LehrAbstract:Purpose Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) Pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. Methods PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects Modeling approach. Results Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. Conclusion The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.
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Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists.
Pharmaceutical Research, 2019Co-Authors: Anke-katrin Volz, Jasper Dingemanse, Andreas Krause, Thorsten LehrAbstract:Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) Pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects Modeling approach. Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.
