2.50
Hdl Handle:
http://hdl.handle.net/10541/74880
Title:
Single-dose clinical pharmacokinetic studies of gefitinib.
Authors:
Swaisland, Helen C; Smith, Robert P; Laight, Alison; Kerr, David J; Ranson, Malcolm R; Wilder-Smith, Clive H; Duvauchelle, Thierry
Abstract:
BACKGROUND: The objective of the five clinical studies presented in this article was to investigate the single-dose pharmacokinetics of gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in healthy volunteers and patients with advanced cancer. METHODS: Studies 1 and 3-5 recruited healthy male volunteers aged 18-65 years; study 2 recruited male or female patients aged>or=18 years with any solid malignant tumour expressing EGFR and refractory to standard therapy. Gefitinib administration was as follows: study 1 (bioavailability in healthy volunteers; n=12)--intravenous infusion of 50 or 100 mg followed by a single oral dose of 250 mg; study 2 (bioavailability in cancer patients; n=19)--intravenous infusion of 50 mg followed by a single oral dose of 250 mg; study 3 (intrasubject variability; n=24)--two single oral doses of 250 mg; study 4 (dose-proportionality; n=15)--three single oral doses of 50-500 mg; study 5 (effect of food; n=26)--two single doses of 250 mg under either fed or fasted conditions. In all studies, venous blood samples for determination of gefitinib plasma concentrations were collected at predetermined intervals. Plasma concentrations of gefitinib were measured using liquid-liquid extraction after basification followed by high-performance liquid chromatography with tandem mass spectrometric detection. Appropriate pharmacokinetic parameters were determined by noncompartmental methods. RESULTS: Study 1: Oral bioavailability of a gefitinib 250 mg dose was 57% in healthy volunteers. Absorption was moderately slow, with geometric mean (gmean) peak plasma concentration (Cmax) of 85 ng/mL (range 43.5-110 ng/mL) reached 5 hours following an oral dose of 250 mg. Study 2: Oral bioavailability of a gefitinib 250 mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmax of 159 ng/mL (range 48.7-324 ng/mL) typically reached 3 hours (range 1-8 hours) following an oral dose of 250 mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) and Cmax were variable--up to 15-fold between subjects and 2-fold within an individual. Study 4: AUCinfinity and Cmax increased with dose across the range of 50-500 mg, and increased dose-proportionally up to 250 mg. Study 5: Small, clinically insignificant increases in AUCinfinity and Cmax were seen in the presence of food (32% and 37%, respectively). CONCLUSIONS: The gefitinib 250 mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen.
Affiliation:
AstraZeneca Pharmaceuticals, Macclesfield, UK. helen.swaisland@astrazeneca.com
Citation:
Single-dose clinical pharmacokinetic studies of gefitinib. 2005, 44 (11):1165-77 Clin Pharmacokinet
Journal:
Clinical Pharmacokinetics
Issue Date:
2005
URI:
http://hdl.handle.net/10541/74880
PubMed ID:
16231967
Type:
Article
Language:
en
ISSN:
0312-5963
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorSwaisland, Helen C-
dc.contributor.authorSmith, Robert P-
dc.contributor.authorLaight, Alison-
dc.contributor.authorKerr, David J-
dc.contributor.authorRanson, Malcolm R-
dc.contributor.authorWilder-Smith, Clive H-
dc.contributor.authorDuvauchelle, Thierry-
dc.date.accessioned2009-07-22T09:09:38Z-
dc.date.available2009-07-22T09:09:38Z-
dc.date.issued2005-
dc.identifier.citationSingle-dose clinical pharmacokinetic studies of gefitinib. 2005, 44 (11):1165-77 Clin Pharmacokineten
dc.identifier.issn0312-5963-
dc.identifier.pmid16231967-
dc.identifier.urihttp://hdl.handle.net/10541/74880-
dc.description.abstractBACKGROUND: The objective of the five clinical studies presented in this article was to investigate the single-dose pharmacokinetics of gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in healthy volunteers and patients with advanced cancer. METHODS: Studies 1 and 3-5 recruited healthy male volunteers aged 18-65 years; study 2 recruited male or female patients aged>or=18 years with any solid malignant tumour expressing EGFR and refractory to standard therapy. Gefitinib administration was as follows: study 1 (bioavailability in healthy volunteers; n=12)--intravenous infusion of 50 or 100 mg followed by a single oral dose of 250 mg; study 2 (bioavailability in cancer patients; n=19)--intravenous infusion of 50 mg followed by a single oral dose of 250 mg; study 3 (intrasubject variability; n=24)--two single oral doses of 250 mg; study 4 (dose-proportionality; n=15)--three single oral doses of 50-500 mg; study 5 (effect of food; n=26)--two single doses of 250 mg under either fed or fasted conditions. In all studies, venous blood samples for determination of gefitinib plasma concentrations were collected at predetermined intervals. Plasma concentrations of gefitinib were measured using liquid-liquid extraction after basification followed by high-performance liquid chromatography with tandem mass spectrometric detection. Appropriate pharmacokinetic parameters were determined by noncompartmental methods. RESULTS: Study 1: Oral bioavailability of a gefitinib 250 mg dose was 57% in healthy volunteers. Absorption was moderately slow, with geometric mean (gmean) peak plasma concentration (Cmax) of 85 ng/mL (range 43.5-110 ng/mL) reached 5 hours following an oral dose of 250 mg. Study 2: Oral bioavailability of a gefitinib 250 mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmax of 159 ng/mL (range 48.7-324 ng/mL) typically reached 3 hours (range 1-8 hours) following an oral dose of 250 mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) and Cmax were variable--up to 15-fold between subjects and 2-fold within an individual. Study 4: AUCinfinity and Cmax increased with dose across the range of 50-500 mg, and increased dose-proportionally up to 250 mg. Study 5: Small, clinically insignificant increases in AUCinfinity and Cmax were seen in the presence of food (32% and 37%, respectively). CONCLUSIONS: The gefitinib 250 mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen.en
dc.language.isoenen
dc.subject.meshAdministration, Oral-
dc.subject.meshAdolescent-
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshArea Under Curve-
dc.subject.meshBiological Availability-
dc.subject.meshCross-Over Studies-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshEpidermal Growth Factor-
dc.subject.meshFasting-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshInjections, Intravenous-
dc.subject.meshLinear Models-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshQuinazolines-
dc.subject.meshSuspensions-
dc.subject.meshTablets-
dc.titleSingle-dose clinical pharmacokinetic studies of gefitinib.en
dc.typeArticleen
dc.contributor.departmentAstraZeneca Pharmaceuticals, Macclesfield, UK. helen.swaisland@astrazeneca.comen
dc.identifier.journalClinical Pharmacokineticsen
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