Hankil Son1,2, Hyerang Roh1,2, Donghwan Lee1,2, and Kyungsoo Park1,2
1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. 2Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Korea
Objectives: Sildenafil has been commonly used for the treatment of erectile dysfunction [1]. A previous research explored sildenafil’s effectiveness based on qualitative indices [2], but there has been no report on the quantitative aspect of erectile response of sildenafil. Based on this background, using a conditional repeated time-to-event (CRTTE) model, this study aimed to assess onset and retention times of erectile response as the direct measure of drug effects in conjunction with sildenafil pharmacokinetics (PK).
Methods: Data were taken from 58 healthy Korean volunteers who received a sildenafil 100mg tablet. Plasma samples for PK analyses were obtained up to 24 hours after dosing, and onset and retention times of erectile response were recorded over12 hours after dosing. A CRTTE model was developed by using an ordinary hazard function for the onset time and a secondary hazard function for the retention time, where the retention hazard function was modeled with its time shifted by the onset time on the assumption that its occurrence was conditioned on the onset event. The hazard function was modeled under various distributional assumptions including exponential, Gompertz and Weibull distributions. The influence of drug effect was incorporated by scaling the baseline hazard by the exponential of the predicted drug effect. The final models were further tested for covariate effects and evaluated by VPC. All analyses were performed using NONMEM 7.2
Results: Sildenafil concentrations were best described by a two-compartment model with first-order absorption and the model appropriateness was well confirmed by VPC. For a CRTTE model, onset times were best described by Gompertz hazard with scale and shape parameters of 0.70/hr and -1.35/hr, respectively, and retention times by Weibull hazard with scale and shape parameters of 0.66/hr and 1.39/hr, respectively, yielding the estimated median onset and retention times of about 0.45hr and 0.40hr, respectively. Overall, the observed onset and retention times were well included within the 90% predicted intervals by VPC. When plasma concentrations included, the model performance improved. No significant relationship was found between covariates and hazard parameters.
Conclusion: This work has demonstrated the feasibility of applying a CRTTE model to quantitatively understanding the drug response in general clinical situations, with an application to the erectile response of sildenafil.
References:
[1] Sildenafil Tablets – Pfizer [http://www.pfizer.com/files/products/uspi_viagra.pdf]
[2] Gruenwald I, Leiba R, Vardi Y: Effect of sildenafil on middle-aged sexually active males with no erectile complaints: a randomized placebo-controlled double-blind study. Eur Urol 2009, 55(4):969-976.
Reference: PAGE 22 () Abstr 2684 [www.page-meeting.org/?abstract=2684]
Poster: Other Modelling Applications