Impact of NEDO Project on Microdosing Clinical Studies: Toward the eIND Study in Japan
Drug Metabolism and Pharmacokinetics 2011 DOI: 10.2133/dmpk.dmpk-11-pf-906 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Crossover pharmacokinetic study Peer reviewed |
|---|---|
| Sample size | 6 |
| Population | Healthy Japanese volunteers |
| Interventions | Cetrozole TMD-322 Anastrozole |
| Dose | 1.98 μg for each drug |
| Topics | Microdosing |
| Citations | 1 |
| Key points | Cetrozole and TMD-322 showed low oral bioavailability (34.9% and 18.4%) and high clearance, leading to markedly lower oral exposure than anastrozole. Two of six subjects had 4- and 17-fold higher cetrozole exposure, indicating interindividual variability not seen with TMD-322 or anastrozole. |
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.