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A Limited Sampling Strategy for Estimation of the Area Under the Plasma Concentration–Time Curve of Gefitinib

Miura, Masatomo PhD*; Sato, Kazuhiro MD, PhD; Miura, Hajime MD; Niioka, Takenori PhD*; Kobayashi, Hiroyuki MS*; Narita, Chihiro BS*; Ito, Hiroshi MD, PhD

doi: 10.1097/FTD.0b013e31829dabbc
Original Article
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Purpose: 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 (C0h, 24 hours after the 13th administration) and 1, 2, 4, 6, 8, 12, and 24 hours (Cnh) 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 C12h showed the highest correlation with the measured AUC0–24 of gefitinib (AUC0–24 = 20.0 × C12h + 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 C0h, C1h, C12h, and C1h + C12h. The median AUC0–24 and C0h 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 C0h threshold of 398 ng/mL.

Conclusions: Use of the C12h 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 C0h was also precise. C0h 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.

*Department of Pharmacy, Akita University Hospital, Akita, Japan; and

Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Correspondence: Masatomo Miura, PhD, Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan (e-mail: m-miura@hos.akita-u.ac.jp).

The authors declare no conflict of interest.

Supported by a Grant (No. 23590168) from the Japan Society for the Promotion of Science, Tokyo, Japan.

Received December 17, 2012

Accepted May 27, 2013

© 2014 by Lippincott Williams & Wilkins