Early tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure.

2.50
Hdl Handle:
http://hdl.handle.net/10541/67974
Title:
Early tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure.
Authors:
Saleem, Azeem; Price, Patricia M
Abstract:
PURPOSE: Pharmacokinetic parameters derived from plasma sampling are used as a surrogate of tumor pharmacokinetics. However, pharmacokinetics-modulating strategies do not always result in increased therapeutic efficacy. Nonsurrogacy of plasma kinetics may be due to tissue-specific factors such as tumor perfusion. EXPERIMENTAL DESIGN: To assess the impact of tumor perfusion and plasma drug exposure on tumor pharmacokinetics, positron emission tomography studies were done with oxygen-15 radiolabeled water in 12 patients, with 6 patients undergoing positron emission tomography studies with carbon-11 radiolabeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and the other 6 with fluorine-18 radiolabeled 5-fluorouracil. RESULTS: We found that tumor blood flow (mL blood/mL tissue/minute) was significantly correlated to early tumor radiotracer uptake between 4 and 6 minutes [standard uptake value (SUV)4-6; rho = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)0-10; predominantly parent drug; rho = 0.86; P < 0.001], and tumor radiotracer exposure over 60 minutes (AUC0-60; predominantly radiolabeled metabolites; rho = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (Vd) was significantly correlated with SUV4-6 (rho = 0.80; P = 0.002), AUC0-10 (rho = 0.85; P < 0.001), and AUC0-60 (rho = 0.66; P = 0.02). In contrast, no correlation was observed between plasma drug or total radiotracer exposure over 60 minutes and tumor drug uptake or exposure. Tumor blood flow was significantly correlated to Vd (rho = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and Vd. CONCLUSIONS: Tumor perfusion is a key factor that influences tumor drug uptake/exposure. Tumor vasculature-targeting strategies may thus result in improved tumor drug exposure and therefore drug efficacy.
Affiliation:
Academic Department of Radiation Oncology, The Christie Hospital NHS Foundation Trust, Manchester. azeem.saleem@manchester.ac.uk
Citation:
Early tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure. 2008, 14 (24):8184-90 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
15-Dec-2008
URI:
http://hdl.handle.net/10541/67974
DOI:
10.1158/1078-0432.CCR-08-1324
PubMed ID:
19088034
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Christie Publications ; Academic Department of Radiation Oncology - ADRO

Full metadata record

DC FieldValue Language
dc.contributor.authorSaleem, Azeem-
dc.contributor.authorPrice, Patricia M-
dc.date.accessioned2009-05-12T16:37:01Z-
dc.date.available2009-05-12T16:37:01Z-
dc.date.issued2008-12-15-
dc.identifier.citationEarly tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure. 2008, 14 (24):8184-90 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid19088034-
dc.identifier.doi10.1158/1078-0432.CCR-08-1324-
dc.identifier.urihttp://hdl.handle.net/10541/67974-
dc.description.abstractPURPOSE: Pharmacokinetic parameters derived from plasma sampling are used as a surrogate of tumor pharmacokinetics. However, pharmacokinetics-modulating strategies do not always result in increased therapeutic efficacy. Nonsurrogacy of plasma kinetics may be due to tissue-specific factors such as tumor perfusion. EXPERIMENTAL DESIGN: To assess the impact of tumor perfusion and plasma drug exposure on tumor pharmacokinetics, positron emission tomography studies were done with oxygen-15 radiolabeled water in 12 patients, with 6 patients undergoing positron emission tomography studies with carbon-11 radiolabeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and the other 6 with fluorine-18 radiolabeled 5-fluorouracil. RESULTS: We found that tumor blood flow (mL blood/mL tissue/minute) was significantly correlated to early tumor radiotracer uptake between 4 and 6 minutes [standard uptake value (SUV)4-6; rho = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)0-10; predominantly parent drug; rho = 0.86; P < 0.001], and tumor radiotracer exposure over 60 minutes (AUC0-60; predominantly radiolabeled metabolites; rho = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (Vd) was significantly correlated with SUV4-6 (rho = 0.80; P = 0.002), AUC0-10 (rho = 0.85; P < 0.001), and AUC0-60 (rho = 0.66; P = 0.02). In contrast, no correlation was observed between plasma drug or total radiotracer exposure over 60 minutes and tumor drug uptake or exposure. Tumor blood flow was significantly correlated to Vd (rho = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and Vd. CONCLUSIONS: Tumor perfusion is a key factor that influences tumor drug uptake/exposure. Tumor vasculature-targeting strategies may thus result in improved tumor drug exposure and therefore drug efficacy.en
dc.language.isoenen
dc.subjectCanceren
dc.subjectTumour Perfusionen
dc.subjectPharmacokineticsen
dc.subject.meshAcridines-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshArea Under Curve-
dc.subject.meshFluorouracil-
dc.subject.meshHumans-
dc.subject.meshNeoplasms-
dc.subject.meshSolubility-
dc.titleEarly tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure.en
dc.typeArticleen
dc.contributor.departmentAcademic Department of Radiation Oncology, The Christie Hospital NHS Foundation Trust, Manchester. azeem.saleem@manchester.ac.uken
dc.identifier.journalClinical Cancer Researchen

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