Plasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes.

2.50
Hdl Handle:
http://hdl.handle.net/10541/67979
Title:
Plasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes.
Authors:
Saleem, Azeem; Aboagye, E O; Matthews, Julian C; Price, Patricia M
Abstract:
PURPOSE: This study aimed to evaluate the utility of plasma pharmacokinetic analyses of anti-cancer agents from data obtained during positron emission tomography (PET) oncology studies of radiolabelled anti-cancer agents. PATIENTS AND METHODS: Thirteen patients were administered fluorine-18 radiolabelled 5-FU ([(18)F]5-FU) admixed with 5-FU, corresponding to a total 5-FU dose of 380-407 mg/m2 (eight patients) and 1 mg/m2 (five patients). Nine patients received 2.2-19.2 microg/m2 of carbon-11 radiolabelled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide ([11C]DACA) at 1/1,000th of phase I dose, as part of phase 0 microdosing study. Radioactivity of parent drug obtained from arterial blood samples, the injected activity of the radiolabelled drug, and the total dose of injected drug were used to obtain plasma drug concentrations. Plasma pharmacokinetic parameters were estimated using model-dependent and model-independent methods. RESULTS: 5-FU plasma concentrations at therapeutic doses were above the Km and a single compartment kinetic model was best used to fit the kinetics, with a mean half-life of 8.6 min. Clearance and volumes of distribution (Vd) obtained using both model-dependent and model-independent methods were similar. Mean (SE) clearance was 1,421(144), ml min(-1) and 1,319 (119) ml min(-1) and the mean (SE) Vd was 17.3 (1.8) l and 16.3 (1.9) l by the model-independent method and model-dependent methods, respectively. In contrast, with 1 mg/m2, plasma concentrations of 5-FU were less than the Km and a two-compartment model was used to best fit the kinetics, with the mean 5-FU half-life of 6.5 min. The mean (SE) clearances obtained by the model-independent method and model-dependent methods were 3,089 (314) ml min(-1) and 2,225 (200) ml min(-1), respectively and the mean (SE) Vd were 27.9 (7.0) l and 2.3 (0.4) l, by the model independent and dependent methods, respectively. Extrapolation of AUC0-Clast to AUC0-infinity was less than 3% in both these cohort of patients. A two-compartment model with a mean half-life of 42.1 min was used to best fit the kinetics of DACA; considerable extrapolation (mean 26%) was required to obtain AUC0-infinity from AUC0-Clast. Mean (SE) clearance of DACA was 1,920 (269) ml min(-1), with the model-independent method and 1,627 (287) ml min(-1) with the model-dependent method. Similarly, Vd [mean (SE)] of DACA with the model-independent and model-dependent methods were 118 (22) l and 50 (15) l, respectively. CONCLUSIONS: Pharmacokinetic parameters can be estimated with confidence from PET studies for agents given at therapeutic doses, whose half-lives are significantly less than the total sampling time during the scan. Tracer studies performed alone, wherein plasma levels below the Km are expected, may also provide valuable information on drug clearance for the entire range of linear kinetics. However, drugs with half-lives longer than the sampling duration are inappropriate for PET plasma pharmacokinetic evaluation.
Affiliation:
Academic Department of Radiation Oncology, Christie Hospital NHS Foundation Trust, Wilmslow Road, and The University of Manchester Wolfson Molecular Imaging Centre, Manchester M20 4BX, UK. azeem.saleem@manchester.ac.uk
Citation:
Plasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes. 2008, 61 (5):865-73 Cancer Chemother. Pharmacol.
Journal:
Cancer Chemotherapy and Pharmacology
Issue Date:
Apr-2008
URI:
http://hdl.handle.net/10541/67979
DOI:
10.1007/s00280-007-0552-2
PubMed ID:
17639391
Type:
Article
Language:
en
ISSN:
0344-5704
Appears in Collections:
All Christie Publications ; Academic Department of Radiation Oncology - ADRO

Full metadata record

DC FieldValue Language
dc.contributor.authorSaleem, Azeem-
dc.contributor.authorAboagye, E O-
dc.contributor.authorMatthews, Julian C-
dc.contributor.authorPrice, Patricia M-
dc.date.accessioned2009-05-12T16:53:48Z-
dc.date.available2009-05-12T16:53:48Z-
dc.date.issued2008-04-
dc.identifier.citationPlasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes. 2008, 61 (5):865-73 Cancer Chemother. Pharmacol.en
dc.identifier.issn0344-5704-
dc.identifier.pmid17639391-
dc.identifier.doi10.1007/s00280-007-0552-2-
dc.identifier.urihttp://hdl.handle.net/10541/67979-
dc.description.abstractPURPOSE: This study aimed to evaluate the utility of plasma pharmacokinetic analyses of anti-cancer agents from data obtained during positron emission tomography (PET) oncology studies of radiolabelled anti-cancer agents. PATIENTS AND METHODS: Thirteen patients were administered fluorine-18 radiolabelled 5-FU ([(18)F]5-FU) admixed with 5-FU, corresponding to a total 5-FU dose of 380-407 mg/m2 (eight patients) and 1 mg/m2 (five patients). Nine patients received 2.2-19.2 microg/m2 of carbon-11 radiolabelled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide ([11C]DACA) at 1/1,000th of phase I dose, as part of phase 0 microdosing study. Radioactivity of parent drug obtained from arterial blood samples, the injected activity of the radiolabelled drug, and the total dose of injected drug were used to obtain plasma drug concentrations. Plasma pharmacokinetic parameters were estimated using model-dependent and model-independent methods. RESULTS: 5-FU plasma concentrations at therapeutic doses were above the Km and a single compartment kinetic model was best used to fit the kinetics, with a mean half-life of 8.6 min. Clearance and volumes of distribution (Vd) obtained using both model-dependent and model-independent methods were similar. Mean (SE) clearance was 1,421(144), ml min(-1) and 1,319 (119) ml min(-1) and the mean (SE) Vd was 17.3 (1.8) l and 16.3 (1.9) l by the model-independent method and model-dependent methods, respectively. In contrast, with 1 mg/m2, plasma concentrations of 5-FU were less than the Km and a two-compartment model was used to best fit the kinetics, with the mean 5-FU half-life of 6.5 min. The mean (SE) clearances obtained by the model-independent method and model-dependent methods were 3,089 (314) ml min(-1) and 2,225 (200) ml min(-1), respectively and the mean (SE) Vd were 27.9 (7.0) l and 2.3 (0.4) l, by the model independent and dependent methods, respectively. Extrapolation of AUC0-Clast to AUC0-infinity was less than 3% in both these cohort of patients. A two-compartment model with a mean half-life of 42.1 min was used to best fit the kinetics of DACA; considerable extrapolation (mean 26%) was required to obtain AUC0-infinity from AUC0-Clast. Mean (SE) clearance of DACA was 1,920 (269) ml min(-1), with the model-independent method and 1,627 (287) ml min(-1) with the model-dependent method. Similarly, Vd [mean (SE)] of DACA with the model-independent and model-dependent methods were 118 (22) l and 50 (15) l, respectively. CONCLUSIONS: Pharmacokinetic parameters can be estimated with confidence from PET studies for agents given at therapeutic doses, whose half-lives are significantly less than the total sampling time during the scan. Tracer studies performed alone, wherein plasma levels below the Km are expected, may also provide valuable information on drug clearance for the entire range of linear kinetics. However, drugs with half-lives longer than the sampling duration are inappropriate for PET plasma pharmacokinetic evaluation.en
dc.language.isoenen
dc.subjectPET-Pharmacokineticsen
dc.subjectTracer Studiesen
dc.subject5-Flurouracilen
dc.subjectCytotoxic Agentsen
dc.subject.meshAcridines-
dc.subject.meshAntimetabolites, Antineoplastic-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshArea Under Curve-
dc.subject.meshCarbon Radioisotopes-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshFluorine Radioisotopes-
dc.subject.meshFluorouracil-
dc.subject.meshHalf-Life-
dc.subject.meshHumans-
dc.subject.meshModels, Biological-
dc.subject.meshTissue Distribution-
dc.subject.meshTomography, Emission-Computed-
dc.titlePlasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes.en
dc.typeArticleen
dc.contributor.departmentAcademic Department of Radiation Oncology, Christie Hospital NHS Foundation Trust, Wilmslow Road, and The University of Manchester Wolfson Molecular Imaging Centre, Manchester M20 4BX, UK. azeem.saleem@manchester.ac.uken
dc.identifier.journalCancer Chemotherapy and Pharmacologyen

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