Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects.
Hiroyuki Kusuhara, Tadayuki Takashima, Hisako Fujii, Tsutomu Takashima, Masaaki Tanaka, Akira Ishii, Shusaku Tazawa, Kazuhiro Takahashi, Kayo Takahashi, Hidekichi Tokai, Tsuneo Yano, Makoto Kataoka, Akihiro Inano, Suguru Yoshida, Takamitsu Hosoya, Yuichi Sugiyama, Shinji Yamashita, Taisuke Hojo, Yasuyoshi Watanabe
Drug Metabolism and Pharmacokinetics December 2017 DOI: 10.1016/j.dmpk.2017.09.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Phase zero cassette microdose clinical trial, crossover Peer reviewed |
|---|---|
| Sample size | 6 |
| Population | Healthy Japanese subjects |
| Interventions | Cetrozole TMD-322 Anastrozole |
| Dose | 1.98 μg for each drug |
| Topics | Microdosing |
| Keywords | Aromatase inhibitor Cassette dosing approach Lc–ms/ms Microdosing clinical trial Pharmacokinetic properties |
| Key findings | Cetrozole and TMD-322 had high hepatic clearance, giving oral exposures markedly lower than anastrozole, with bioavailabilities of 34.9% and 18.4%, respectively. Two of six subjects showed 4- and 17-fold higher cetrozole exposure after intravenous and oral dosing, while TMD-322 and anastrozole showed no such variation. Both compounds were extensively metabolized by CYP2C19. |
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.
Comparable studies
Other randomized controlled trials on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs Volunteers | 2006 | Crossover study | |
| Self-blinding citizen science to explore psychedelic microdosing. Participants who microdose psychedelics | 2021 | Self-blinding citizen science initiative with placebo control | n = 191 |
| Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study Individuals starting to microdose with psilocybin mushrooms (Psilocybe cubensis) | 2022 | Double-blind placebo-controlled experimental design | n = 34 |
| Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity. Healthy young adults, 18 to 35 years old | 2019 | Randomized controlled trial | n = 20 |
| Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial. Healthy male volunteers | 2023 | Randomized controlled trial | n = 80 |
Citations in the library
Cited by 3
- Phase 0/microdosing approaches: time for mainstream application in drug development? Nature Reviews Drug Discovery September 8, 2020
- Phase 0 trials/ Intra-Target-Microdosing (ITM) and the lung: a review BMC Pulmonary Medicine September 1, 2024
- Phase 0, Including Microdosing Approaches: Applying the Three Rs and Increasing the Efficiency of Human Drug Development Alternatives to Laboratory Animals December 1, 2018
Cites 7
- Identification of the Rate-Determining Process in the Hepatic Clearance of Atorvastatin in a Clinical Cassette Microdosing Study Clinical Pharmacology & Therapeutics August 10, 2011
- Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development Clinical and Translational Science February 26, 2016
- The utility of microdosing over the past 5 years Expert Opinion on Drug Metabolism & Toxicology November 28, 2008
- Impact of microdosing clinical study — Why necessary and how useful? Advanced Drug Delivery Reviews October 14, 2010
- Nonlinear Pharmacokinetics of Oral Quinidine and Verapamil in Healthy Subjects: A Clinical Microdosing Study Clinical Pharmacology & Therapeutics June 29, 2011
and 2 more in the library