Clinical Drug–Drug Interaction Potential of BFE1224, Prodrug of Antifungal Ravuconazole, Using Two Types of Cocktails in Healthy Subjects

BFE1224, prodrug of ravuconazole, is a novel, once‐daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug–drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cockt...

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Bibliographic Details
Published in:Clinical and translational science 2018-09, Vol.11 (5), p.477-486
Main Authors: Ishii, Yasuyuki, Ito, Yuko, Matsuki, Shunji, Sanpei, Kasumi, Ogawa, Osamu, Takeda, Kenji, Schuck, Edgar L., Uemura, Naoto
Format: Article
Language:English
Subjects:
Administration, Oral
Adult
Antifungal agents
Antifungal Agents - pharmacology
Biological Assay
Breast cancer
Caffeine
Clinical medicine
CYP1A2 protein
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
Dextromethorphan
Digoxin
Drug dosages
Drug interaction
Drug Interactions
Employees
Female
Fungicides
Healthy Volunteers
Humans
Male
Metabolism
Metabolites
Metabolome
Midazolam
Omeprazole
Onychomycosis
Oral administration
Organic anion transporting polypeptide
Pharmaceutical industry
Pharmacokinetics
Prodrugs - pharmacology
Protein transport
Ravuconazole
Studies
Thiazoles - blood
Thiazoles - pharmacokinetics
Thiazoles - pharmacology
Tolbutamide
Triazoles
Triazoles - blood
Triazoles - pharmacokinetics
Triazoles - pharmacology
Young Adult
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Summary:BFE1224, prodrug of ravuconazole, is a novel, once‐daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug–drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2. In addition, repaglinide was separately administered to the same subjects in study 2. There were no major effects on the pharmacokinetics of CYP and transporter substrates, except for an approximate threefold increase in midazolam exposure after oral administration of BFE1224. The clinical DDIs of BFE1224 were mild for CYP3A and minor for other major CYPs (CYP1A2/2C8/2C9/2C19/2D6) as well as those of P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3.
ISSN:1752-8054
1752-8062
DOI:10.1111/cts.12557