Effects of itraconazole and rifampicin on the pharmacokinetics and safety of youkenafil, a novel phosphodiesterase type 5 inhibitor, in healthy Chinese subjects

•First report of in vivo and in vitro drug interaction studies on youkenafil.•First report of youkenafil pharmacokinetic parameters in healthy Chinese subjects.•Itraconazole and rifampicin have significant clinical effect on youkenafil. Youkenafil is a novel selective phosphodiesterase type 5 inhibi...

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Published in:European journal of pharmaceutical sciences Vol. 175; p. 106213
Main Authors: Wang, Keli, Ding, Juefang, Li, Xianjing, Guo, Wenjing, Zhu, Xingyu, Su, Yue, Sun, Luning, Zhou, Huan, Ding, Li
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01.08.2022
Subjects:
Drug interaction
Itraconazole
Pharmacokinetics
Rifampicin
Youkenafil
NADPH
M1
DDI
cGMP
CIs
Tris-HCl
AEs
Youkenafil
Rifampicin
ANOVA
CYP450
Drug interaction
ke
Itraconazole
AUC0-t
BMI
ED
Cmax
PDE5
MgCl2
t1/2z
GMRs
ECG
IS
US FDA
HPLC-MS/MS
SAE
AUC0-
Tmax
PK
Pharmacokinetics
CL/F
ISSN:0928-0987, 1879-0720, 1879-0720
Online Access:Get full text
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Summary:•First report of in vivo and in vitro drug interaction studies on youkenafil.•First report of youkenafil pharmacokinetic parameters in healthy Chinese subjects.•Itraconazole and rifampicin have significant clinical effect on youkenafil. Youkenafil is a novel selective phosphodiesterase type 5 inhibitor to treat erectile dysfunction. In order to study the drug-drug interactions of youkenafil, in vitro experiments were conducted with human liver microsomes and recombinant isoenzymes to identify the effect of cytochrome P450 (CYP) enzymes on the metabolism of youkenafil. Then two clinical studies were performed to investigate the effects of itraconazole and rifampicin (potent CYP3A4/5 inhibitor and inducer, respectively) on the pharmacokinetics of youkenafil and its main metabolite, N-desethyl youkenafil (M1). Each study enrolled thirty healthy male subjects. In study 1, subjects were given a single dose of youkenafil (50 mg on Days 1 and 13) and multiple doses of itraconazole (200 mg once daily from Days 6 to 14). In study 2, subjects were given a single dose of youkenafil (100 mg on Days 1 and 20) and multiple doses of rifampicin (600 mg once daily from Days 6 to 20). The results showed that youkenafil was mainly metabolized through CYP3A4/5 in vitro. Itraconazole increased youkenafil AUC and Cmax by about 12- and 6-fold, respectively, and increased M1 AUC and Cmax by 5- and 1.3-fold, respectively. Conversely, rifampicin reduced youkenafil AUC and Cmax both by about 98%. It did not change the AUC of M1 significantly, but increased the Cmax by 30%. All treatments were well tolerated by subjects in both studies. Therefore, co-administration of youkenafil with potent inhibitors or inducers of CYP3A4/5 should be avoided or carefully monitored. Graphical Abstract [Display omitted] .
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ISSN:0928-0987
1879-0720
1879-0720
DOI:10.1016/j.ejps.2022.106213