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Hong, Lee, Jeon, Paek, Kim, Kwak, Park, Han, and Yim: Comparison of the Population Pharmacokinetics and Safety Between Please Orally Soluble Film and VIAGRA® in Healthy Male Volunteers
Original Article

J Korean Soc Clin Pharmacol Ther 2013;21(1):26-33.

Published online: 11 January 2013

DOI: https://doi.org/10.12793/jkscpt.2013.21.1.26

Comparison of the Population Pharmacokinetics and Safety Between Please Orally Soluble Film and VIAGRA® in Healthy Male Volunteers

Taegon Hong1, Jongtae Lee1, Sangil Jeon1, Jeongki Paek1, Hyun II Kim2, Seong Shin Kwak2, Su Jun Park2, Seunghoon Han1, Dong-Seok Yim1

1Department of Pharmacology, College of Medicine, the Catholic University of Korea and Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary’s Hospital, Seoul, Republic of Korea

2CTC BIO Corporation, 93, Ogeum-dong, Songpa-gu, Seoul, Korea

E-mail: waystolove@catholic.ac.kr

Received 20 May 201324 June 2013       Accepted 25 June 2013

Copyright © 2013 Korean Society for Clinical Pharmacology and Therapeutics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background:

The objective of this study was to compare the pharmacokinetics and safety between newly developed sildenafil (Please Orally Soluble Film) and sildenafil citrate (VIAGRA®) after single oral administration in healthy Korean male subjects.

Methods:

A randomized, open-label, single dose, 2-way crossover study was conducted in 50 healthy male subjects. Each sequence group consisted of 25 subjects, received a single oral 50 mg dose of Please Orally Soluble Film (test formulation) or VIAGRA® (reference formulation) by study period. Blood samples were obtained during a 24-hour period after dosing. Sildenafil and its metabolite concentrations were determined using validated LC-MS/MS. A non-compartmental pharmacokinetic analysis was performed. Safety was assessed through monitoring of adverse events, vital sign check-up, physical examination, laboratory tests and electrocardiography.

Results:

All enrolled participants completed the study. The point estimates and 90 % confidence intervals of log transformed Cmax and AUClast of the test formulation in comparison to those of reference formulation were 0.9294(0.8353 - 1.0341) and 0.9415 (0.8869 - 0.9994) respectively. The analysis of variance showed no significant influences of formulation, sequence and period on the pharmacokinetic parameters. The frequencies of adverse events were not statistically different between the formulations. No serious adverse event was observed or reported.

Conclusion:

Please Orally Soluble Film could be considered bioequivalent to VIAGRA® and had similar safety properties in healthy Korean male subjects.

Keywords: Sildenafil, Pharmacokinetics, Safety, Healthy subjects

REFERENCES

1. Kim TH, Chung TG, Ahn TY. Relation between lower urinary tract symptoms and erectile dysfunction epidemiologic study in Jeong-Eup. Kor J Androl. 1998; 16(1):87–91.
2. Woodwell DA, Cherry DK. National Ambulatory Medical Care Survey: 2002 summary. Advance data. 2004; 26(346):1–44.
3. Ryu SB, Min KD, Park KS, Park YI, Rhee JA, Kweon SS. Epidemiologic study of the male erectile dysfunction with risk, factors in rural area. Korean J Androl. 2001; 19:125–31.
4. Feldman HA, Goldstein I, Hatzichristou DG, Kranae RJ, McKinlay JB. Importence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151(1):54–61.
5. Lee U, Lee MH, Kim SY, Ji YH, Hong JH, Ahn TY. Clinical efficacy and safety of sildenafil in the men with erectile dysfunction in Korea. Korean J Urol. 2001; 42(4):435–440.
6. Price DE, Gingell JC, Gepi-Attee S, Wareham K, Yates P, Boolell M. Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men. Diabet Med. 1998; 15(10):821–825.
crossref
7. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil citrate after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol. 2002; 53:5S–12S.

Figure 1.
Mean (standard deviation) plasma concentration-time profile of reference (VIAGRA®) and test (Please Orally Soluble Film) formulation after a single oral administration.
jkscpt-21-26f1.tif
Table 1.
Subject demographics
Categories
 Group
 Total (n = 50) P-value
1 (RT)* (n = 25) 2 (TR)* (n = 25)
Continuous variable Age years 25.2 ± 2.5 25.2 ± 3 .4 25.2 ± 3.0 0.9257†
Height cm 173.2 ± 4.9 173.6 ± 4.8 173.4 ± 4.8 0.5445†
Weight Kg 68.2 ± 6.2 67.0 ± 8.3 67.6 ± 7.3 0.7808†
Categorical variable Smoking Yes 17 20 37 0.5202‡
No 8 5 13
Alcohol Yes 15 16 31 1.0000‡
No 10 9 19
Caffeine Yes 14 19 33 0.2321‡

Continuous variable results are presented as mean ± standard deviation. *R: reference (VIAGRA®), T: test (Please Orally Soluble Film). †t-test. ‡Fisher’s exact test.

Table 2.
Pharmacokinetic parameters of sildenafil and N-desmethyl sildenafil in reference (VIAGRA®) and test (Please Orally Soluble Film) formulation
Parameter (Sildenafil) Reference Test
Cmax (ng/mL) 368.93 ± 188.84 (51.19 %) 341.98 ± 162.71 (47.58 %)
AUClast (hr*µg/mL) 932.65 ± 448.41 (48.08 %) 887.38 ± 430.60 (48.53 %)
AUCinf (hr*µg/mL) 953.91 ± 455.58 (47.76 %) 918.87 ± 438.47 (47.72 %)
Tmax (hr) 0.81 ± 0.45 (55.81 %) 0.73 ± 0.26 (35.29 %)
t1/2 (hr) 2.89 ± 1.60 (55.35 %) 3.49 ± 3.50 (100.23 %)
λz
 0.28 ± 0.10 (36.13 %)
 0.27 ± 0.10 (37.66 %)
Parameter (N-desmethyl sildenafil)
 Reference
 Test
Cmax (ng/mL) 79.63 ± 37.66 (47.30 %) 81.56 ± 39.41 (48.33 %)
AUClast (hr*µg/mL) 248.20 ± 123.34 (49.69 %) 242.95 ± 127.50 (52.48 %)
AUCinf (hr*µg/mL) 263.96 ± 124.67 (47.23 %) 257.71 ± 128.48 (49.85 %)
Tmax (hr) 0.94 ± 0.47 (50.19 %) 0.83 ± 0.34 (41.37 %)
t1/2 (hr) 3.97 ± 1.60 (40.16 %) 4.11 ± 1.77 (43.04 %)
λz 0.20 ± 0.07 (36.92 %) 0.20 ± 0.08 (38.40 %)

Results are presented as mean ± standard deviation (CV(%)). Cmax: maximum plasma concentration. AUClast: area under the plasma concentration-time curve from zero time until last measurable concentration. AUGinf: area under the plasma concentration-time curve from zero time to infinity. Tmax: time to maximum plasma concentration. t1/2: terminal elimination half-life. λZ: terminal elimination rate constant.

Table 3.
Geometric mean ratio and 90 % confidence interval for Cmax and AUClast of sildenafil and N-desmethyl sildenafil in test (Please Orally Soluble Film) and reference (VIAGRA®) formulations in healthy male volunteers
Parameter (Sildenafil) Geometric mean ratio (Test / Reference) 90 % Confidence interval for geometric mean ratio
Cmax 0.9294 (0.8353, 1.0341)
AUClast
 0.9415
 (0.8869, 0.9994)
Parameter (N-desmethyl sildenafil)
 Geometric mean ratio (Test / Reference)
 90 % Confidence interval for geometric mean ratio
Cmax 1.0385 (0.9437, 1.1428)
AUClast 0.9684 (0.9108, 1.0296)

Cmax: maximum plasma concentration. AUClast: area under the plasma concentration-time curve from zero time until last measurable concentration.

Table 4.
Analysis of variance for pharmacokinetic parameters of sildenafil between reference (VIAGRA®) and test (Please Orally Soluble Film) formulations
In(Cmax)
Source DF SS† MS‡ F-stat P-value
Sequence 1 0.0778 0.0778 0.2031 0.6542
Sequence*ID 48 18.3951 0.3832 3.7878 <0.0001
Form 1 0.1339 0.1339 1.3235 0.2557
Period 1 0.1448 0.1448 1.4309 0.2375
Error
 48
 4.8564
 0.1012
 -
 -
In(AUClast)
Source DF SS MS F-stat P-value
Sequence 1 0.0583 0.0583 0.1404 0.7095
Sequence*ID 48 19.9316 0.4152 13.1142 <0.0001
Form 1 0.0909 0.0909 2.8709 0.0967
Period 1 0.0494 0.0494 1.5611 0.2176
Error 48 1.5199 0.0317 - -

* Degree of freedom. † Sum of squares. ‡ Mean square.

Table 5.
Analysis of variance for pharmacokinetic parameters of N-desmethyl sildenafil between reference (VIAGRA®) and test (Please Orally Soluble Film) formulations
In(Cmax)
Source DF SS† MS‡ F-stat P-value
Sequence 1 0.6097 0.6097 1.5096 0.2252
Sequence*ID 48 19.3879 0.4039 4.9641 <0.0001
Form 1 0.0356 0.0356 0.4381 0.5112
Period 1 0.3505 0.3505 4.3082 0.0433
Error
 48
 3.9056
 0.0814
In(AUClast)
Source DF SS MS F-stat P-value
Sequence 1 0.2791 0.2791 0.5894 0.4464
Sequence*ID 48 22.7342 0.4736 14.1679 <0.0001
Form 1 0.0258 0.0258 0.7732 0.3836
Period 1 0.0190 0.0190 0.5671 0.4551
Error 48 1.6046 0.0334

* Degree of freedom. †Sum of squares. ‡Mean square.

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