title: A limited sampling strategy for estimation of the area under the plasma concentration-time curve of gefitinib.
abstract: OBJECTIVE
  The aim of this study was to develop a limited sampling strategy (LSS) to estimate the area under the concentration-time curve (AUC) of gefitinib using data from 18 patients with non-small-cell lung cancer.
  
  
  METHODS
  On day 14 after beginning daily therapy with 250 mg of gefitinib, plasma samples were collected just before (C(0h), 24 hours after the 13th administration) and 1, 2, 4, 6, 8, 12, and 24 hours (C(nh)) after gefitinib administration and were analyzed by high-performance liquid chromatography.
  
  
  RESULTS
  The predicted AUC from 0 to 24 hours (AUC₀₋₂₄) from the single time point of C(12h) showed the highest correlation with the measured AUC₀₋₂₄ of gefitinib (AUC₀₋₂₄ = 20.0 · C(12h) + 1348.0; r² = 0.9623; P , 0.0001). The 95% confidence intervals of the slopes and intercepts of the formulae obtained by bootstrap analysis indicated acceptable accuracy and robustness in the prediction of AUC₀₋₂₄ using C(0h), C(1h), C(12h), and C(1h) + C(12h). The median AUC₀₋₂₄ and C(0h) of gefitinib in patients with diarrhea (n = 8) were higher than those without diarrhea (n = 10) (15,043 versus 8918 ng·h·mL⁻¹, respectively, P = 0.0164 and 542 versus 261 ng/mL, respectively, P = 0.0263). The area under the receiver operator curve was 0.813, giving the best sensitivity (75%) and specificity (90%) at a C(0h) threshold of 398 ng/mL.
  
  
  CONCLUSIONS
  Use of the C(12h) single time point is recommended for the gefitinib AUC₀₋₂₄ predictive equation; however, total estimation of the AUC₀₋₂₄ of gefitinib at the single point of C(0h) was also precise. C(0h) monitoring of gefitinib might be beneficial during gefitinib therapy, because of a high variability in gefitinib exposure among patients taking 250 mg. Further examination of the correlation between clinical evaluation and the gefitinib exposure is necessary.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sato
authors.forename: Hajime
authors.initials: H
authors.lastname: Miura
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Chihiro
authors.initials: C
authors.lastname: Narita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003967:Diarrhea / Q000453:epidemiology; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012372:ROC Curve; D012680:Sensitivity and Specificity; D013048:Specimen Handling; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib