• Ken-ichi Fujita, Etsuko Yoshino, Kaori Kawara, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Taro Yokoyama, Toshikado Kaneta, Hiroo Ishida, and Yasutsuna Sasaki.
• Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan. k.fujita@med.showa-u.ac.jp.
• Cancer Chemother. Pharmacol. 2015 Oct 1; 76 (4): 793-801.

PurposeWhether microdosing studies can be used to evaluate the human pharmacokinetics of new anticancer drugs remains unclear. The disposition of docetaxel in cancer patients is linear in terms of dose proportionality. We examined whether the pharmacokinetics of docetaxel in a clinically relevant therapeutic dose could be predicted from the pharmacokinetics of a microdose of docetaxel in Japanese patients with cancer.MethodsA microdose of docetaxel (100 μg/patient) was given by 5-min intravenous infusion on day 1, followed by a therapeutic dose of docetaxel (60-75 mg m(-2)), given by 1-h intravenous infusion on day 8. Plasma docetaxel was analyzed by liquid chromatography-tandem mass spectrometry. A two-compartment pharmacokinetic model was used to calculate the area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf).ResultsNine patients received both a microdose and therapeutic dose of docetaxel. The AUC0-inf after microdosing was 3640 ± 1150 ng h L(-1), while that after therapeutic dosing adjusted to 100 mg/patient was 2230 ± 757 µg h L(-1). The ratio of docetaxel clearance in therapeutic dose to that in microdose was 1.8 (P = 0.0041). Plasma α1-acid glycoprotein concentrations negatively correlated with docetaxel clearance at therapeutic dose, whereas the trend was weak at microdose.ConclusionDocetaxel clearance showed marginal nonlinearity between microdose and therapeutic dose, presumably because of saturation of plasma protein binding; however, the magnitude was within twofold, allowing practically acceptable extrapolation.

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