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Drug Metab Pharmacokinet. 2017 Dec;32(6):293-300. doi: 10.1016/j.dmpk.2017.09.003. Epub 2017 Sep 21.

Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects.

Author information

1
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
2
RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
3
Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; Osaka City University Hospital, Center for Drug & Food Clinical Evaluation, 1-2-7 Asahimachi, Abeno-ku, Osaka 545-0051, Japan.
4
Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
5
Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
6
Osaka City University Hospital, Center for Drug & Food Clinical Evaluation, 1-2-7 Asahimachi, Abeno-ku, Osaka 545-0051, Japan.
7
RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
8
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
9
Clinical Research Center, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan.
10
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
11
RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
12
Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, Yokohama Bio Industry Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
13
Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: yywata@riken.jp.

Abstract

The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development.

KEYWORDS:

Aromatase inhibitor; Cassette dosing approach; First in human study; LC–MS/MS; Microdosing clinical trial; Pharmacokinetic properties

PMID:
29137842
DOI:
10.1016/j.dmpk.2017.09.003
[Indexed for MEDLINE]

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