Effect of ketoconazole on the pharmacokinetics of udenafil in healthy Korean subjects.
OBJECTIVE
Udenafil is a phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction. It is metabolized to DA-8164, a major metabolite, by CYP3A4. This study was performed to investigate the effect of ketoconazole, a known CYP3A4 inhibitor, on the pharmacokinetics of udenafil.


METHODS
An open-label, two-period, fixed-sequence crossover study was performed in 12 healthy male volunteers. They received a single 100-mg oral dose of udenafil. Following a 5-day interval, 400 mg of ketoconazole was administered once a day for three consecutive days. On day 3 of ketoconazole treatment, a second 100 mg of udenafil was dosed concomitantly. Blood samples were collected at time points up to 48 h without ketoconazole treatment and up to 72 h with ketoconazole co-administration. The plasma concentration of udenafil was determined using liquid chromatography-tandem mass spectrometry.


RESULTS
Following ketoconazole co-administration, the mean C(max) and AUC(last) of udenafil (95% confidence interval) increased 1.9-fold (1.60, 2.27) and 3.2-fold (2.82, 3.63), respectively. The median time to reach the C(max) was delayed in the co-administrated treatment, while the mean terminal elimination half-life (t(1/2)) remained relatively unchanged regardless of ketoconazole co-administration. The metabolic AUC ratio (AUC(last) of DA-8164/AUC(last) of udenafil) was 1.71 when udenafil was administered alone, and the value decreased to 0.19 when udenafil was dosed in the presence of ketoconazole. Regarding safety assessments, no clinically significant difference or serious adverse event was observed.


CONCLUSIONS
The systemic exposure of udenafil increased significantly when it was administered with ketoconazole. Dose adjustment may be required when these drugs are used together.
Shin
Kwang-Hee
KH
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Chung
Yong-ju
YJ
Kim
Bo-Hyung
BH
Kim
Tae-Eun
TE
Kim
Hwa-Sook
HS
Cho
Joo-Youn
JY
Jang
In-Jin
IJ
Shin
Sang-Goo
SG
Yu
Kyung-Sang
KS
D022126:Access to Information; D000284:Administration, Oral; D000328:Adult; D044466:Asian People; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides; D055815:Young Adult; D000096926:Benzenesulfonamides
D007654:Ketoconazole; D011743:Pyrimidines; D013449:Sulfonamides; C419664:udenafil; D000096926:Benzenesulfonamides