Peter A. Milligan1, Scott F. Marshall1, Mats O. Karlsson2
1. Pfizer Central Research, Sandwich, Kent. United Kingdom; 2. Division of Biopharmaceutics and Pharmacokinetics, University of Uppsala. Sweden
Sildenafil is an orally administered compound developed and approved for the treatment of erectile dysfunction (ED). A population pharmacokinetic sampling strategy was incorporated into five Phase III clinical studies. A total of 4582 samples were assayed for both drug and metabolite (UK-103,320) concentrations from 2077 (1335 sildenafil treated) patients.
Phase I studies have shown sildenafil pharmacokinetics to be influenced by a number of factors – age, renal function, hepatic status However, the extent of these effects are unknown in the general (more heterogeneous) ED patient population. Additionally, pre-clinical and in vitro data suggest that UK-103,320 also exhibited some pharmacological activity. Analysis of Phase III data would discern the nature and extent of the a priori covariate relationships in patients not subjected to the limited inclusion and exclusion criteria of a Phase I study, in addition to quantifying any additional relationships a posteriori.
Efficacy data was obtained from patient responses to the International Index of Erectile Function (IIEF), a sexual function questionnaire. Responses to the IIEF were scored on a five point scale ranging from almost never/never (1) to almost always/always (5), with a score of (0) assigned for no attempts at sexual intercourse. Question 3 of the IIEF (How often were you able to penetrate your partner ?) and Question 4 (How often were you able to maintain your erection after you had penetrated your partner ?) were selected as the primary endpoints. Both continuous and categorical PK/PD models with components for baseline and placebo were used to relate response to administered dose, drug exposure, metabolite exposure or a combination of both drug and metabolite exposures.
The aim of this analysis was to use pharmacokinetic data to aid interpretation of both efficacy and safety data, thereby assisting the formation of future dosage strategies.
Reference: PAGE 8 () Abstr 136 [www.page-meeting.org/?abstract=136]
Poster: oral presentation