subject:(PET Pharmacokinetics)

Universiteit Utrecht

1. Boss, D.S. Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/37369

► With the emergence of novel, rationally designed anti-cancer drugs there is also a need for novel endpoints when evaluating these drugs in clinical trials. The… (more)

▼ With the emergence of novel, rationally designed anti-cancer drugs there is also a need for novel endpoints when evaluating these drugs in clinical trials. The combined PET/CT scanner can be a very useful tool in the process of drug development in several ways, which is described in the first chapter of this thesis. PET/CT can be used for patient selection, for measuring the early response to treatment, and for determining the pharmacokinetics and pharmacodynamics of novel anti-cancer drugs. The next chapter describes the novel drug class of the aurora kinase inhibitors. First, the clinical experience with inhibitors of aurora kinase A, B, or both is reviewed. Following this review article, a phase I study with one of these agents, AZD1152, is described. In the subsequent chapters of this thesis, several phase I trials are described with a variety of novel anti-cancer drugs, with various mechanisms of action. These agents include: AZD5438, an inhibitor of cyclin dependent kinases; olaparib (AZD2281), a PARP inhibitor; E7080, an angiogenesis inhibitor; and PF00299804, an inhibitor of HER-1, HER-2, and HER-4 receptor tyrosine kinases. Also, several phase I studies combining targeted anti-cancer drugs with conventional chemotherapy are described. The main goal for all of the described phase I trials in this thesis was to determine the maximum tolerable dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the investigational drugs. However, increasingly important in these studies are pharmacodynamic endpoints, which can give early indications of the activity of the investigational drugs. Several of the studies in this thesis have successfully implemented pharmacodynamic assays, with the olaparib phase I trial as best example. In this study, target inhibition (reduced activity of the target enzyme poly(ADP-ribose)polymerase) was demonstrated in white blood cells as well as in tumor cells from patients following treatment with olaparib. One of the important conclusions from these results was that there is no need to dose the patients at the MTD since maximal target inhibition is already obtained with lower doses of olaparib. Several of the investigational anti-cancer drugs described in this thesis showed promising activity. Olaparib, for instance, appeared very effective in patients with BRCA deficient breast and ovarian cancer (over half of the patients with BRCA deficient tumors derived clinical benefit from treatment with olaparib). In the phase I trial with E7080, treatment with the angiogenesis inhibitor led to reductions in tumor volume in all patients with melanoma who entered the study. Finally, several partial responses were observed in patients with non-small cell lung cancer following treatment with the pan-HER inhibitor PF00299804. In conclusion, this thesis describes phase I studies with novel anti-cancer agents. Several of the described compounds are now under evaluation in phase II and phase III studies. Future studies with targeted agents should focus more on pharmacodynamic endpoints,… Advisors/Committee Members: Schellens, J.H.M., Beijnen, J.H..

Subjects/Keywords: Farmacie; Drug Development; PET/CT; Phase I studies; Pharmacokinetics; Pharmacodynamics; Clinical trials; Cancer; Targeted therapy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Boss, D. S. (2009). Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/37369

Chicago Manual of Style (16^th Edition):

Boss, D S. “Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed January 20, 2021. http://dspace.library.uu.nl:8080/handle/1874/37369.

MLA Handbook (7^th Edition):

Boss, D S. “Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs.” 2009. Web. 20 Jan 2021.

Vancouver:

Boss DS. Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Jan 20]. Available from: http://dspace.library.uu.nl:8080/handle/1874/37369.

Council of Science Editors:

Boss DS. Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/37369

Virginia Commonwealth University

2. McDonagh, Philip R, III. Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations of CONPs’ Pharmacokinetics, Efficacy, and Mechanisms of Action.

Degree: PhD, Clinical and Translational Sciences, 2016, Virginia Commonwealth University

URL: https://doi.org/10.25772/RSGK-C791 ; https://scholarscompass.vcu.edu/etd/4314

► Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radioprotective drug,… (more)

▼ Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radioprotective drug, an area of research in need due to the severe side effects from radiation therapy. In this work, the potential of CONPs as a radioprotective drug is examined using four criteria: favorable biodistribution/pharmacokinetics, low toxicity, ability to protect normal tissue from radiation damage, and lack of protection of tumor. The mechanisms of action of CONPs are also studied. Biodistribution was determined in radiolabeled CONPs with surface coatings including citrate, dextran T10-amine (DT10-NH₂), dextran T10-polyethylene glycol (DT10-PEG), dextran T10-sulfobetaine (DT10-SB) and poly(acrylic acid) (PAA), and compared to uncoated. ⁸⁹Zr was incorporated into CONPs for positron emission tomography (PET) imaging and ex vivo tissue analysis in tumor bearing mice. Compared to uncoated [⁸⁹Zr]CONPs, coated [⁸⁹Zr]CONPs showed improved biodistribution, including significantly enhanced renal clearance of PAA- [⁸⁹Zr]CONPs. The toxicity of CONPs was evaluated in vitro and in vivo, with low toxicity at therapeutic doses. After clinically mimetic radiation therapy, pre-treatment of mice with coated and uncoated CONPs showed greater than 50% reduction of cell death in normal colon tissue, comparable to the clinically available radioprotective drug amifostine. Tumor control after irradiation of spontaneous colon tumors was unchanged with PAA-CONP pre-treatment, while citrate, DT10-PEG, and uncoated CONP pre-treatment had slightly less tumor control. Xenograft tumors were irradiated after pH normalizing treatment with sodium bicarbonate and PAA-CONP pre-treatment. Treatment of these tumors showed slightly less tumor control than irradiation alone or PAA-CONP plus irradiation, demonstrating that the acidic pH of the tumor microenvironment may be the basis of preventing CONPs’ radioprotective properties in tumor. These studies show that, among the variations of CONPs tested, PAA-CONP shows the most promise for its good biodistribution and quick clearance, low toxicity, ability to protect normal tissue, and lack of protection of tumor, meeting all the criteria set forth for an ideal radioprotective drug. Further studies on the effects of pH on CONPs actions may further elucidate their mechanisms of action, advancing them as a candidate for use as a radioprotective drug during radiation therapy. Advisors/Committee Members: Jamal Zweit, Ross Mikkelsen.

Subjects/Keywords: cerium oxide nanoparticles; nanomedicine; molecular imaging; PET imaging; pharmacokinetics; radioprotection; Nanomedicine; Translational Medical Research

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

McDonagh, Philip R, I. (2016). Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations of CONPs’ Pharmacokinetics, Efficacy, and Mechanisms of Action. (Doctoral Dissertation). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/RSGK-C791 ; https://scholarscompass.vcu.edu/etd/4314

Chicago Manual of Style (16^th Edition):

McDonagh, Philip R, III. “Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations of CONPs’ Pharmacokinetics, Efficacy, and Mechanisms of Action.” 2016. Doctoral Dissertation, Virginia Commonwealth University. Accessed January 20, 2021. https://doi.org/10.25772/RSGK-C791 ; https://scholarscompass.vcu.edu/etd/4314.

MLA Handbook (7^th Edition):

McDonagh, Philip R, III. “Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations of CONPs’ Pharmacokinetics, Efficacy, and Mechanisms of Action.” 2016. Web. 20 Jan 2021.

Vancouver:

McDonagh, Philip R I. Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations of CONPs’ Pharmacokinetics, Efficacy, and Mechanisms of Action. [Internet] [Doctoral dissertation]. Virginia Commonwealth University; 2016. [cited 2021 Jan 20]. Available from: https://doi.org/10.25772/RSGK-C791 ; https://scholarscompass.vcu.edu/etd/4314.

Council of Science Editors:

McDonagh, Philip R I. Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations of CONPs’ Pharmacokinetics, Efficacy, and Mechanisms of Action. [Doctoral Dissertation]. Virginia Commonwealth University; 2016. Available from: https://doi.org/10.25772/RSGK-C791 ; https://scholarscompass.vcu.edu/etd/4314

University of Michigan

3. Joshi, Aniket. Improved Quantitative Methods for Multiple Neuropharmacological Non-Invasive Brain PET Studies.

Degree: PhD, Biomedical Engineering, 2008, University of Michigan

URL: http://hdl.handle.net/2027.42/61729

► Positron emission tomography (PET) is a medical imaging modality offering a powerful tool for brain research by mapping of in vivo neuropharmacological functions such as… (more)

▼ Positron emission tomography (PET) is a medical imaging modality offering a powerful tool for brain research by mapping of in vivo neuropharmacological functions such as metabolism, enzyme activity, and neuroreceptor binding site density and occupancy. Quantification in brain-PET can be classified into: 1) accurate quantification of radiotracer distribution such that image values are proportional to the radiotracer concentration in tissue, and 2) accurate quantification of the pharmacological state of the system-of-interest. This thesis addresses both these aspects for functional neuroreceptor imaging studies of the living brain. Traditional brain PET studies have at least two primary limitations. First, they measure only a single neuropharmacological aspect in isolation, which is often insufficient for characterizing a neurological condition. Second, data acquisition is accompanied by the invasive arterial blood sampling for measuring the input function to the system-of-interest. The motivation for this thesis was to address both these limitations, which led to the development of quantitative methods for multiple neuropharmacological PET studies performed without blood sampling. One such experimental design investigated was a dual-measurement intervention study where the system-of-interest is perturbed with the intent of changing the subject’s pharmacological status and system parameters are estimated both pre- and post-intervention. Second was a dual-tracer study where two radiotracers targeting two different neuropharmacological systems were injected closely in time in the same study. A major challenge in analyzing multiple pharmacological PET studies is the statistical noise-induced bias and variance in the parameter estimates. Methods developed in this thesis reduced almost all the bias (>90%) in the intervention studies with a corresponding improvement in precision. Parameter estimates for dual-tracer studies were obtained with inter-subject regions-of-interest means within ±10% of those obtained from single-tracer scans without appreciable increase in variance. The thesis also addresses inter-scanner PET image variability, a major confound in multi-center studies used to investigate disease progression. Since various PET centers have scanners with different hardware and software, systematic differences exist in multi-center data. This thesis develops a framework to reduce the inter-scanner PET image variability before pooling multi-center data for analysis. The methods developed reduced variability in phantom scans from different sites by approximately 50%. Advisors/Committee Members: Fessler, Jeffrey A. (committee member), Koeppe, Robert A. (committee member), Clinthorne, Neal H. (committee member), Meyer, Charles R. (committee member), Noll, Douglas C. (committee member).

Subjects/Keywords: Positron Emission Tomography; PET Pharmacokinetics; PET Kinetic Modeling; Neuropharamacological Measurements Using PET; Neuroimaging; PET for Clinical Diagnosis and Drug Discovery; Radiology; Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Joshi, A. (2008). Improved Quantitative Methods for Multiple Neuropharmacological Non-Invasive Brain PET Studies. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/61729

Chicago Manual of Style (16^th Edition):

Joshi, Aniket. “Improved Quantitative Methods for Multiple Neuropharmacological Non-Invasive Brain PET Studies.” 2008. Doctoral Dissertation, University of Michigan. Accessed January 20, 2021. http://hdl.handle.net/2027.42/61729.

MLA Handbook (7^th Edition):

Joshi, Aniket. “Improved Quantitative Methods for Multiple Neuropharmacological Non-Invasive Brain PET Studies.” 2008. Web. 20 Jan 2021.

Vancouver:

Joshi A. Improved Quantitative Methods for Multiple Neuropharmacological Non-Invasive Brain PET Studies. [Internet] [Doctoral dissertation]. University of Michigan; 2008. [cited 2021 Jan 20]. Available from: http://hdl.handle.net/2027.42/61729.

Council of Science Editors:

Joshi A. Improved Quantitative Methods for Multiple Neuropharmacological Non-Invasive Brain PET Studies. [Doctoral Dissertation]. University of Michigan; 2008. Available from: http://hdl.handle.net/2027.42/61729

4. Kouwenberg, J.J.M. (author). Pharmacokinetics and Dosimetry of Gallium-68 labelled Sarabesin 3 for Prostate Cancer.

Degree: 2015, Delft University of Technology

URL: http://resolver.tudelft.nl/uuid:81a32de2-5f74-4582-ab23-079a8db80483

► Objective: Prostate cancer remains one of the most prevalent forms of cancer in men aged over 65 years, with yearly around 11,200 new cases and… (more)

▼ Objective: Prostate cancer remains one of the most prevalent forms of cancer in men aged over 65 years, with yearly around 11,200 new cases and 2,600 deaths in the Netherlands. Diagnosis of prostate cancer still relies on biopsies, which are unpleasant and invasive procedures for the patient. The new PET tracer, [68Ga]Sarabesin 3, aims to offer an accurate and minimally invasive way to locate and diagnose PC by taking benefit of the overexpression of the gastrin releasing peptide receptor on prostate cancer cells. In this research, the pharmacokinetics of the tracer in cancerous and healthy tissues from dynamic PET imaging was studied to identify receptor-specific uptake in prostate cancer tissue. Methods: An image derived input function was obtained from a volume of interest drawn over the femoral artery. The image derived input function correction methods proposed by Chen[1], Mourik[2] and Hackett[3] were evaulated using Monte Carlo simulation of the fermoral artery. The simulation was done in GATE using a model of the Siemens Biograph mCT. Iteratively reweighted least squares and step-wise model fitting were used to increase the accuracy in the small spots suspicious of cancerous tissue. In order to validate the applied arterial input function correction methods, a model of the Siemens Biograph mCT was built in the GATE Monte Carlo software. The absorbed dose was calculated using the MIRD male dosimetry model, OLINDA/EXM and the time activity curves in the various organs. A simple one-way perfusion model of the kidney was applied to estimate the bladder filling over time. Results: The sensitivity and spatial resolution of the GATE model at the field-of-view center were respectively 11,1 ± 0,027 kcps/MBq and 4,00 ± 0,56 mm full width half maximum in the radial direction, both closely matching the values of reported by Jakoby[4]. Applying the arterial input function correction methods to the simulated arterial and venous concentration curves showed that Hackett’s method[3] most accurately estimates the true arterial concentration with less than 1% error after the first pass peak. Step-wise fitting of the 1-, FDG- and 2-compartment models showed to be less vulnerable to local minima. An increase up to 280% receptor density was observed in the spots suspicious of cancerous tissue compared to the surrounding tissue healthy prostate tissue, thereby providing proof for the specific uptake of [68Ga]Sarabesin 3 by gastrin releasing peptide receptor in prostate cancer tissue. The pharmacokinetics of [68Ga]Sarabesin 3 were best described by a FDG model or a 2 compartment model with a small retention coefficient. It was not possible to determine the retention coefficient of the latter due the relatively large noise and small number of measurement points 50 minutes post-injection. Conclusion: Hackett’s method estimated the arterial concentration well in Monte Carlo simulations. [68Ga]Sarabesin 3 showed a good uptake in spots suspicious of cancerous tissue and had a high retention despite being an antagonist. The absorbed dose… Advisors/Committee Members: Segbers, M. (mentor), Konijnenberg, M. (mentor), Denkova, A. (mentor).

Subjects/Keywords: prostate cancer; sarabesin; pharmacokinetics; monte carlo; PET; tracer

…of PET/CT scans, venous and urine samples for a period of approximately 4 hours. Slices of… …was measured. 2. Pharmacokinetic Modeling 2.1. Quantitative PET Measurement All scans… …corresponding to the respective PET scan using PMod as shown in Figure 1. Spots assessed by an… …with their 7 Pharmacokinetics and Dosimetry of Ga-68 labelled Sarabesin 3 for Prostate Cancer… …are registered trademarks of The MathWorks, Inc. 8 Pharmacokinetics and Dosimetry of Ga-68…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kouwenberg, J. J. M. (. (2015). Pharmacokinetics and Dosimetry of Gallium-68 labelled Sarabesin 3 for Prostate Cancer. (Masters Thesis). Delft University of Technology. Retrieved from http://resolver.tudelft.nl/uuid:81a32de2-5f74-4582-ab23-079a8db80483

Chicago Manual of Style (16^th Edition):

Kouwenberg, J J M (author). “Pharmacokinetics and Dosimetry of Gallium-68 labelled Sarabesin 3 for Prostate Cancer.” 2015. Masters Thesis, Delft University of Technology. Accessed January 20, 2021. http://resolver.tudelft.nl/uuid:81a32de2-5f74-4582-ab23-079a8db80483.

MLA Handbook (7^th Edition):

Kouwenberg, J J M (author). “Pharmacokinetics and Dosimetry of Gallium-68 labelled Sarabesin 3 for Prostate Cancer.” 2015. Web. 20 Jan 2021.

Vancouver:

Kouwenberg JJM(. Pharmacokinetics and Dosimetry of Gallium-68 labelled Sarabesin 3 for Prostate Cancer. [Internet] [Masters thesis]. Delft University of Technology; 2015. [cited 2021 Jan 20]. Available from: http://resolver.tudelft.nl/uuid:81a32de2-5f74-4582-ab23-079a8db80483.

Council of Science Editors:

Kouwenberg JJM(. Pharmacokinetics and Dosimetry of Gallium-68 labelled Sarabesin 3 for Prostate Cancer. [Masters Thesis]. Delft University of Technology; 2015. Available from: http://resolver.tudelft.nl/uuid:81a32de2-5f74-4582-ab23-079a8db80483

University of Lund

5. Sydoff, Marie. Quantification Methods for Clinical Studies in Nuclear Medicine - Applications in AMS, PET/CT and SPECT/CT.

Degree: 2013, University of Lund

URL: https://lup.lub.lu.se/record/4057774 ; https://portal.research.lu.se/ws/files/5942884/4058481.pdf

► An essential part of the development of new radiopharmaceuticals for use in diagnostic nuclear medicine is the determination of its biokinetic properties. The uptake and… (more)

▼ An essential part of the development of new radiopharmaceuticals for use in diagnostic nuclear medicine is the determination of its biokinetic properties. The uptake and turn-over of the radiopharmaceutical in the source organs is of great interest since this could determine whether the radiopharmaceutical would be suitable for clinical use or not. It is also important that the biokinetics and dosimetry of the radiopharmaceuticals is thoroughly investigated in order to determine the radiation absorbed doses to various organs and tissues and the effective dose. This is done to evaluate the radiation risks, which is one of the risks factors that have to be compared, with the benefits of their use. Modern imaging systems such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have limitations that complicate the accurate estimation of the activity content in source organs, and thus also the estimation of the radiation absorbed dose, to organs and tissues of the human body. As an example, the partial volume effect poses significant problems with the reliability of the activity values when imaging small volumes. Drawing regions of interest smaller than the actual structure could influence the results. With large ROIs, the activity concentration has been shown to be underestimated by 70 % for a 0.5-ml sphere and 31 % for a 20-ml sphere. With small ROIs the underestimation ranges from 66 to 16 % (Paper II). PET is becoming more common in radiotherapy treatment planning and also used to monitor treatment response. In these cases, as well as in planning of surgery, it is important that the volume of the structure of interest is estimated accurately. Using phantoms with fillable, hollow, plastic spheres in an active background for estimation of the volume reproducing threshold would lead to overestimation of the tumour volume. The background dependence seen when using plastic phantoms is not present when using gelatin phantoms without walls (Paper III). As new imaging modalities are introduced, the measurement procedures and outline of clinical studies have to be adjusted to make use of the full potential of these new techniques. Biokinetic studies have commonly been performed using planar gamma camera images and the use of the conjugate view technique. As SPECT is very common at nuclear medicine clinics today, the use of this new and supposedly more accurate technique for determination of the biokinetics of radiopharmaceuticals is a natural step in the development process. It was shown that the organ dose estimations differed significantly when using complementary SPECT/CT measurements to quantify activity in the organs (i.e. to conduct dosimetry measurements) than when using planar images alone (Paper I). In drug development, accelerator mass spectrometry (AMS) has become an important tool for quantifying the content of 14C-labelled drug molecules in biological samples and to determine the pharmacokinetics of promising new drugs. PET or SPECT can be used simultaneously with AMS for…

Subjects/Keywords: Radiology, Nuclear Medicine and Medical Imaging; Nuclear Medicine; AMS; PET/CT; SPECT/CT; dosimetry; internal dosimetry; quantification; activity quantification; volume delineation; radiation; biokinetics; pharmacokinetics; biodistribution

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sydoff, M. (2013). Quantification Methods for Clinical Studies in Nuclear Medicine - Applications in AMS, PET/CT and SPECT/CT. (Doctoral Dissertation). University of Lund. Retrieved from https://lup.lub.lu.se/record/4057774 ; https://portal.research.lu.se/ws/files/5942884/4058481.pdf

Chicago Manual of Style (16^th Edition):

Sydoff, Marie. “Quantification Methods for Clinical Studies in Nuclear Medicine - Applications in AMS, PET/CT and SPECT/CT.” 2013. Doctoral Dissertation, University of Lund. Accessed January 20, 2021. https://lup.lub.lu.se/record/4057774 ; https://portal.research.lu.se/ws/files/5942884/4058481.pdf.

MLA Handbook (7^th Edition):

Sydoff, Marie. “Quantification Methods for Clinical Studies in Nuclear Medicine - Applications in AMS, PET/CT and SPECT/CT.” 2013. Web. 20 Jan 2021.

Vancouver:

Sydoff M. Quantification Methods for Clinical Studies in Nuclear Medicine - Applications in AMS, PET/CT and SPECT/CT. [Internet] [Doctoral dissertation]. University of Lund; 2013. [cited 2021 Jan 20]. Available from: https://lup.lub.lu.se/record/4057774 ; https://portal.research.lu.se/ws/files/5942884/4058481.pdf.

Council of Science Editors:

Sydoff M. Quantification Methods for Clinical Studies in Nuclear Medicine - Applications in AMS, PET/CT and SPECT/CT. [Doctoral Dissertation]. University of Lund; 2013. Available from: https://lup.lub.lu.se/record/4057774 ; https://portal.research.lu.se/ws/files/5942884/4058481.pdf

6. Boss, D.S. Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs.

Degree: 2009, University Utrecht

URL: https://dspace.library.uu.nl/handle/1874/37369 ; URN:NBN:NL:UI:10-1874-37369 ; 1874/37369 ; urn:isbn:9789490122643 ; URN:NBN:NL:UI:10-1874-37369 ; https://dspace.library.uu.nl/handle/1874/37369

► With the emergence of novel, rationally designed anti-cancer drugs there is also a need for novel endpoints when evaluating these drugs in clinical trials. The… (more)

▼ With the emergence of novel, rationally designed anti-cancer drugs there is also a need for novel endpoints when evaluating these drugs in clinical trials. The combined PET/CT scanner can be a very useful tool in the process of drug development in several ways, which is described in the first chapter of this thesis. PET/CT can be used for patient selection, for measuring the early response to treatment, and for determining the pharmacokinetics and pharmacodynamics of novel anti-cancer drugs. The next chapter describes the novel drug class of the aurora kinase inhibitors. First, the clinical experience with inhibitors of aurora kinase A, B, or both is reviewed. Following this review article, a phase I study with one of these agents, AZD1152, is described. In the subsequent chapters of this thesis, several phase I trials are described with a variety of novel anti-cancer drugs, with various mechanisms of action. These agents include: AZD5438, an inhibitor of cyclin dependent kinases; olaparib (AZD2281), a PARP inhibitor; E7080, an angiogenesis inhibitor; and PF00299804, an inhibitor of HER-1, HER-2, and HER-4 receptor tyrosine kinases. Also, several phase I studies combining targeted anti-cancer drugs with conventional chemotherapy are described. The main goal for all of the described phase I trials in this thesis was to determine the maximum tolerable dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the investigational drugs. However, increasingly important in these studies are pharmacodynamic endpoints, which can give early indications of the activity of the investigational drugs. Several of the studies in this thesis have successfully implemented pharmacodynamic assays, with the olaparib phase I trial as best example. In this study, target inhibition (reduced activity of the target enzyme poly(ADP-ribose)polymerase) was demonstrated in white blood cells as well as in tumor cells from patients following treatment with olaparib. One of the important conclusions from these results was that there is no need to dose the patients at the MTD since maximal target inhibition is already obtained with lower doses of olaparib. Several of the investigational anti-cancer drugs described in this thesis showed promising activity. Olaparib, for instance, appeared very effective in patients with BRCA deficient breast and ovarian cancer (over half of the patients with BRCA deficient tumors derived clinical benefit from treatment with olaparib). In the phase I trial with E7080, treatment with the angiogenesis inhibitor led to reductions in tumor volume in all patients with melanoma who entered the study. Finally, several partial responses were observed in patients with non-small cell lung cancer following treatment with the pan-HER inhibitor PF00299804. In conclusion, this thesis describes phase I studies with novel anti-cancer agents. Several of the described compounds are now under evaluation in phase II and phase III studies. Future studies with targeted agents should focus more on pharmacodynamic endpoints,… Advisors/Committee Members: Schellens, J.H.M., Beijnen, J.H..

Subjects/Keywords: Drug Development; PET/CT; Phase I studies; Pharmacokinetics; Pharmacodynamics; Clinical trials; Cancer; Targeted therapy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Boss, D. S. (2009). Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs. (Doctoral Dissertation). University Utrecht. Retrieved from https://dspace.library.uu.nl/handle/1874/37369 ; URN:NBN:NL:UI:10-1874-37369 ; 1874/37369 ; urn:isbn:9789490122643 ; URN:NBN:NL:UI:10-1874-37369 ; https://dspace.library.uu.nl/handle/1874/37369

Chicago Manual of Style (16^th Edition):

Boss, D S. “Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs.” 2009. Doctoral Dissertation, University Utrecht. Accessed January 20, 2021. https://dspace.library.uu.nl/handle/1874/37369 ; URN:NBN:NL:UI:10-1874-37369 ; 1874/37369 ; urn:isbn:9789490122643 ; URN:NBN:NL:UI:10-1874-37369 ; https://dspace.library.uu.nl/handle/1874/37369.

MLA Handbook (7^th Edition):

Boss, D S. “Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs.” 2009. Web. 20 Jan 2021.

Vancouver:

Boss DS. Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs. [Internet] [Doctoral dissertation]. University Utrecht; 2009. [cited 2021 Jan 20]. Available from: https://dspace.library.uu.nl/handle/1874/37369 ; URN:NBN:NL:UI:10-1874-37369 ; 1874/37369 ; urn:isbn:9789490122643 ; URN:NBN:NL:UI:10-1874-37369 ; https://dspace.library.uu.nl/handle/1874/37369.

Council of Science Editors:

Boss DS. Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs. [Doctoral Dissertation]. University Utrecht; 2009. Available from: https://dspace.library.uu.nl/handle/1874/37369 ; URN:NBN:NL:UI:10-1874-37369 ; 1874/37369 ; urn:isbn:9789490122643 ; URN:NBN:NL:UI:10-1874-37369 ; https://dspace.library.uu.nl/handle/1874/37369

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