BackgroundThe 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.MethodsStudies 1 and 3–5 recruited healthy male volunteers aged 18–65 years; study 2 recruited male or female patients aged ≥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 100mg followed by a single oral dose of 250mg; study 2 (bioavailability in cancer patients; n = 19) − intravenous infusion of 50mg followed by a single oral dose of 250mg; study 3 (intrasubject variability; n = 24) – two single oral doses of 250mg; study 4 (dose-proportionality; n = 15) – three single oral doses of 50–500mg; study 5 (effect of food; n = 26) – two single doses of 250mg 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.ResultsStudy 1: Oral bioavailability of a gefitinib 250mg 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 250mg. Study 2: Oral bioavailability of a gefitinib 250mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmaxof 159 ng/mL (range 48.7–324 ng/mL) typically reached 3 hours (range 1–8 hours) following an oral dose of 250mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUC∞) and Cmaxwere variable – up to 15-fold between subjects and 2-fold within an individual. Study 4: AUC∞and Cmaxincreased with dose across the range of 50–500mg, and increased dose-proportionally up to 250mg. Study 5: Small, clinically insignificant increases in AUC∞and Cmaxwere seen in the presence of food (32% and 37%, respectively).ConclusionsThe gefitinib 250mg 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.