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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| Vydáno v: | European journal of pharmaceutical sciences Ročník 175; s. 106213 |
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| Hlavní autoři: | , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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Netherlands
Elsevier B.V
01.08.2022
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| ISSN: | 0928-0987, 1879-0720, 1879-0720 |
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| Abstract | •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
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| AbstractList | •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] . 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 C by about 12- and 6-fold, respectively, and increased M1 AUC and C by 5- and 1.3-fold, respectively. Conversely, rifampicin reduced youkenafil AUC and C both by about 98%. It did not change the AUC of M1 significantly, but increased the C 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. 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.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. |
| ArticleNumber | 106213 |
| Author | Guo, Wenjing Sun, Luning Li, Xianjing Zhu, Xingyu Zhou, Huan Ding, Juefang Su, Yue Wang, Keli Ding, Li |
| Author_xml | – sequence: 1 givenname: Keli surname: Wang fullname: Wang, Keli organization: Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China – sequence: 2 givenname: Juefang surname: Ding fullname: Ding, Juefang organization: Nanjing Jiening Pharmaceutical Technology Co., LTD, Nanjing, 211000, China – sequence: 3 givenname: Xianjing surname: Li fullname: Li, Xianjing organization: Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China – sequence: 4 givenname: Wenjing surname: Guo fullname: Guo, Wenjing organization: Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China – sequence: 5 givenname: Xingyu surname: Zhu fullname: Zhu, Xingyu organization: National Drug Clinical Trial Center, The First Affiliated Hospital of Bengbu Medical College, Bengbu, An-hui, 233000, China – sequence: 6 givenname: Yue surname: Su fullname: Su, Yue organization: National Drug Clinical Trial Center, The First Affiliated Hospital of Bengbu Medical College, Bengbu, An-hui, 233000, China – sequence: 7 givenname: Luning surname: Sun fullname: Sun, Luning organization: Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, 210029, China – sequence: 8 givenname: Huan surname: Zhou fullname: Zhou, Huan email: zhouhuan@bbmc.edu.cn organization: National Drug Clinical Trial Center, The First Affiliated Hospital of Bengbu Medical College, Bengbu, An-hui, 233000, China – sequence: 9 givenname: Li orcidid: 0000-0003-2813-0985 surname: Ding fullname: Ding, Li email: 1019910740@cpu.edu.cn organization: Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China |
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| Cites_doi | 10.1345/aph.1E383 10.1002/bdd.748 10.1002/jcph.562 10.1136/postgradmedj-2016-134073 10.1016/S0009-9236(96)90018-1 10.1111/bcp.12309 10.1177/0091270009340418 10.1007/s10557-019-06851-7 10.1016/j.ejps.2014.12.019 10.1111/bcp.14994 10.1016/j.ejps.2017.05.043 10.1016/j.jpba.2008.04.004 10.1038/clpt.1994.60 10.1124/dmd.107.020099 10.1016/j.pop.2019.02.006 10.3390/pharmaceutics11070354 10.1080/00498250600709778 10.1038/nrdp.2016.3 10.1517/14656561003698131 10.1002/jssc.201600445 10.1016/j.dmpk.2020.11.003 10.2165/00002018-200932010-00001 10.1111/bcp.14302 |
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| Keywords | 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 |
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| Title | Effects of itraconazole and rifampicin on the pharmacokinetics and safety of youkenafil, a novel phosphodiesterase type 5 inhibitor, in healthy Chinese subjects |
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