Jeongki Paek(1,2), Seunghoon Han (1,2), Jongtae Lee (1,2), Sangil Jeon (1,2), Taegon Hong (1,2), Dong-Seok Yim (1,2)
(1) Department of Pharmacology, College of Medicine, The Catholic University of Korea, (2) Department of Clinical Pharmacology and Therapeutics, Seoul St.Mary's Hospital
Objectives: Recently, many comparative pharmacokinetic (PK) studies are conducted in Korea using Viagra® (Pfizer Inc., NY, USA) as the reference drug. This study was to investigate the PK characteristics of sildenafil(Viagra®) with data from several different studies on healthy male Korean subjects. The major metabolite (N-desmethyl sildenafil, NDS) was also taken into consideration because it also had similar pharmacologic activity to that of the parent drug.
Methods: Non-linear mixed effect analysis(NONMEM ver 7.2) was performed using a total of 6,130 observations (3,065 for each chemical entity) from 223 subjects (27.5 observations / subject) obtained after single 50-100 mg sildenafil citrate dose in 7 PK studies. The samples were collected just before and 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 and 24 hours after dosing. First-order conditional estimation method with interaction option was used for all applicable minimization process.
Results: Two-compartment models were used to describe the disposition of both sildenafil and NDS. The central and peripheral volumes of distribution, instead of the metabolic fraction, were fixed to those of the parent drug. An additional elimination pathway of sildenafil was allowed other than NDS metabolism. Use of a pathway for the first-pass metabolism resulted in improved model fit. The absorption of sildenafil and the first-pass metabolism to NDS were best described with zero-order process. All other PK processes were assumed to follow first-order kinetics. The total number of parameters was 17 including 6 between-subject random effects. The precision and shrinkage levels were within acceptable limits for all parameters.
Conclusions: Currently, the structure and predictive performance of the model is considered acceptable. We are to perform a covariate analysis and to incorporate handling methods for missing data to further improve the model.
References:
[1] Peter A. Milligan, Scott F. Marshall, Mats O. Karlsson(2002) 'A population pharmacokinetic analysis of sildenafil citrate in patients with erectile dysfunction', British Journal of Clinical Pharmacology, 53: 1, 45 – 52
[2] Donald J. Nichols, Gary J. Muirhead, Jane A. Harness(2002) ‘Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality', British Journal of Clinical Pharmacology, 53: 1, 5 – 12
[3] D. K. Walker, M. J. Ackland, G. C. James, G. J. Muirhead, D. J. Rance, P. Wastall, P. A. Wright(1999) ‘Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man', XENOBIOTICA, 29: 3, 297 – 310
[4] Gary J. Muirhead, Keith Wilner, Wayne Colburn, Gertrude Haug-Pihale, Bernhard Rouviex(2002) ‘The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil citrate', British Journal of Clinical Pharmacology, 53: 1, 21 – 30
Reference: PAGE 22 () Abstr 2839 [www.page-meeting.org/?abstract=2839]
Poster: Other Drug/Disease Modelling