The Experts below are selected from a list of 225 Experts worldwide ranked by ideXlab platform
Damien M Cronier - One of the best experts on this subject based on the ideXlab platform.
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optimising the combination dosing strategy of abemaciclib and vemurafenib in braf mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Daisy Hartman, Palaniappan Kulanthaivel, Richard P Beckmann, Damien M CronierAbstract:Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.
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Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Palaniappan Kulanthaivel, Richard P Beckmann, Daisy G Hartman, Damien M CronierAbstract:Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. The Quantitative Pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.
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semi mechanistic pharmacokinetic pharmacodynamic modeling of the antitumor activity of ly2835219 a new cyclin dependent kinase 4 6 inhibitor in mice bearing human tumor xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
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Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
Sonya C Tate - One of the best experts on this subject based on the ideXlab platform.
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optimising the combination dosing strategy of abemaciclib and vemurafenib in braf mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Daisy Hartman, Palaniappan Kulanthaivel, Richard P Beckmann, Damien M CronierAbstract:Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.
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Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Palaniappan Kulanthaivel, Richard P Beckmann, Daisy G Hartman, Damien M CronierAbstract:Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. The Quantitative Pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.
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semi mechanistic pharmacokinetic pharmacodynamic modeling of the antitumor activity of ly2835219 a new cyclin dependent kinase 4 6 inhibitor in mice bearing human tumor xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
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Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
Richard P Beckmann - One of the best experts on this subject based on the ideXlab platform.
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optimising the combination dosing strategy of abemaciclib and vemurafenib in braf mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Daisy Hartman, Palaniappan Kulanthaivel, Richard P Beckmann, Damien M CronierAbstract:Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.
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Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Palaniappan Kulanthaivel, Richard P Beckmann, Daisy G Hartman, Damien M CronierAbstract:Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. The Quantitative Pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.
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semi mechanistic pharmacokinetic pharmacodynamic modeling of the antitumor activity of ly2835219 a new cyclin dependent kinase 4 6 inhibitor in mice bearing human tumor xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
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Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
Teresa F Burke - One of the best experts on this subject based on the ideXlab platform.
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optimising the combination dosing strategy of abemaciclib and vemurafenib in braf mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Daisy Hartman, Palaniappan Kulanthaivel, Richard P Beckmann, Damien M CronierAbstract:Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.
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Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours
British Journal of Cancer, 2016Co-Authors: Sonya C Tate, Teresa F Burke, Palaniappan Kulanthaivel, Richard P Beckmann, Daisy G Hartman, Damien M CronierAbstract:Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the Quantitative Pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. The Quantitative Pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.
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semi mechanistic pharmacokinetic pharmacodynamic modeling of the antitumor activity of ly2835219 a new cyclin dependent kinase 4 6 inhibitor in mice bearing human tumor xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
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Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts
Clinical Cancer Research, 2014Co-Authors: Sonya C Tate, Teresa F Burke, Richard P Beckmann, Rose T Ajamie, Edward M Chan, Alfonso De Dios, Graham N Wishart, Lawrence M Gelbert, Damien M CronierAbstract:Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the Quantitative Pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by i) relating the rate of tumor growth to mitotic cell density, and ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated anti-tumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell cycle arrest and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady state trough plasma concentrations of 200 ng/mL is required to maintain durable cell cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the Quantitative Pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.
Mohammad Tabrizi - One of the best experts on this subject based on the ideXlab platform.
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antibody drug conjugates application of Quantitative Pharmacology in modality design and target selection
Aaps Journal, 2015Co-Authors: S Sadekar, I Figueroa, Mohammad TabriziAbstract:Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate Quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a Quantitative approach and framework for evaluation of the interplay between drug- and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of Quantitative sciences in selection of the target and design of ADC modalities.
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application of Quantitative Pharmacology in development of therapeutic monoclonal antibodies
Aaps Journal, 2010Co-Authors: Mohammad Tabrizi, Cherryl Funelas, Hamza SuriaAbstract:The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose– and concentration–response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of Quantitative Pharmacology is critical for translation of exposure–response relationships early on.
