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.
Subject(s)
Aniline Compounds/pharmacokinetics , Aromatase Inhibitors/pharmacokinetics , Aromatase/metabolism , Drug Discovery , Nitriles/pharmacokinetics , Triazoles/pharmacokinetics , Administration, Intravenous , Administration, Oral , Aged , Anastrozole , Aniline Compounds/administration & dosage , Aniline Compounds/chemistry , Animals , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/chemistry , Cross-Over Studies , Dose-Response Relationship, Drug , Healthy Volunteers , Humans , Japan , Male , Molecular Structure , Nitriles/administration & dosage , Nitriles/chemistry , Rats , Structure-Activity Relationship , Triazoles/administration & dosage , Triazoles/chemistryABSTRACT
Review, safety, and relief services of the Pharmaceuticals and Medical Devices Agency are primarily focused on scientifically evaluating pharmaceuticals, medical devices, and cellular and tissue-based products referring to their quality, efficacy, and safety, which requires a variety of scientific knowledge and methods. Pharmaceutical regulation should be established based on the most advanced scientific expertise at all times. In order to evaluate products that use cutting-edge technology such as induced pluripotent stem cells and information and communication technology adequately, since fiscal year 2012 the Science Committee has been established as a platform to exchange opinions among members from top-ranking domestic and international academia and to enhance personnel exchanges through the Initiative to Facilitate Development of Innovative Drugs. In addition, the Regulatory Science Center will be established in 2018 to increase the integrity of our services for product reviews and safety measures. In particular, requiring electronic data submissions for clinical trial applications followed by an advanced approach to analysis should not only enhance the quality of reviews of individual products but should also support the development of pharmaceuticals and medical devices by providing pharmaceutical affairs consultations on research and development strategies with various guidelines based on new insights resulting from product-bridging data analysis. Moreover, a database including electronic health records with comprehensive medical information collected mainly from 10 cooperating medical institutions will be developed with the aim of developing safety measures in a more timely manner using methods of pharmacoepidemiological analysis.
Subject(s)
Drug Design , Drug and Narcotic Control , Equipment Design , Equipment Safety , Medical Device Legislation , Safety , Science , Databases as Topic , Government Agencies , Health Information Systems , Quality Control , Risk Assessment , Risk ManagementABSTRACT
OBJECTIVE: The aim of this study was to assess the non-inferiority of 1 mg to 3 mg granisetron (GRN) injection for the treatment of acute chemotherapy-induced nausea and vomiting (CINV) and to evaluate the tolerability of GRN given at 1 mg in Japanese cancer patients. METHODS: Patients with cancer receiving highly emetogenic chemotherapy were enrolled in this single-blind randomized controlled study. Patients were randomly assigned to receive GRN at a single dose of 1 or 3 mg. The primary endpoint was the rate of complete protection from emetic events (no vomiting, no retching and no need for rescue medication) during the first 24 h following the initiation of chemotherapy. RESULTS: There were 89 patients in the 1 mg group and 90 patients in the 3 mg group. Complete protection was achieved in 70 patients (78.7%) in the 1 mg group and 73 (81.1%) patients in the 3 mg group. The one-sided test did not reveal non-inferiority of either dose of GRN to the other at a 5% significance level. CONCLUSIONS: Our data failed to show the non-inferiority of 1 mg of GRN to 3 mg of GRN administered as a single dose. However, the rate of complete protection from nausea and vomiting was similar in the two groups. Given the recommended dosage in the guidelines and the economic need for reduction of medical care expenses in Japan, prophylactic administration of GRN at 1 mg may be an appropriate, alternative treatment for acute CINV in cancer patients.
