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dc.contributor.authorRosso, Lula
dc.contributor.authorBrock, Cathryn S
dc.contributor.authorGallo, James M
dc.contributor.authorSaleem, Azeem
dc.contributor.authorPrice, Patricia M
dc.contributor.authorTurkheimer, Federico E
dc.contributor.authorAboagye, E O
dc.date.accessioned2009-03-11T09:33:22Z
dc.date.available2009-03-11T09:33:22Z
dc.date.issued2009-01-01
dc.identifier.citationA new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients. 2009, 69 (1):120-7 Cancer Res.en
dc.identifier.issn1538-7445
dc.identifier.pmid19117994
dc.identifier.doi10.1158/0008-5472.CAN-08-2356
dc.identifier.urihttp://hdl.handle.net/10541/54013
dc.description.abstractDifficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.
dc.language.isoenen
dc.subjectPETen
dc.subjectTemozolomideen
dc.subjectPharmacokineticsen
dc.subjectBrain Tumour
dc.subject.meshAdministration, Oral
dc.subject.meshAntineoplastic Agents, Alkylating/administration & dosage
dc.subject.meshBrain/metabolism
dc.subject.meshBrain Neoplasms/blood
dc.subject.meshCarbon Radioisotopes/diagnostic use
dc.subject.meshDacarbazine/analogs & derivatives*
dc.subject.meshGlioma/blood
dc.subject.meshHumans
dc.subject.meshIsotope Labeling
dc.subject.meshModels, Biological*
dc.subject.meshPositron-Emission Tomography
dc.subject.meshRadiopharmaceuticals/diagnostic use
dc.subject.meshTissue Distribution
dc.subject.meshAntineoplastic Agents, Alkylating/pharmacokinetics*
dc.subject.meshAntineoplastic Agents, Alkylating/blood
dc.subject.meshBrain/radionuclide imaging
dc.subject.meshBrain Neoplasms/drug therapy
dc.subject.meshBrain Neoplasms/metabolism*
dc.subject.meshBrain Neoplasms/radionuclide imaging
dc.titleA new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients.en
dc.typeArticleen
dc.contributor.departmentClinical Sciences Centre, Imperial College, Faculty of Medicine, Hammersmith Hospital Campus, London, UK.en
dc.identifier.journalCancer Researchen
html.description.abstractDifficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.


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