To evaluate the effect on urethral pressure of reference drugs known to reduce stress urinary incontinence symptoms by different effect size and mechanisms of action on urethral musculature under four test conditions in healthy female subjects using urethral pressure reflectometry.
Healthy females aged 18-55 years were recruited by advertising for this phase 1, single site, placebo-controlled, randomized, four-period, crossover study. The interventions were single oral doses of 10 mg Midodrine, 80 mg Duloxetine, 12 mg Reboxetine, and placebo. The endpoints were the opening urethral pressure measured in each period at four time points (predose and 2, 5.5, and 9 h after dosing).
Twenty-nine females were enrolled; 25 randomized and 24 completed the study. The opening urethral pressure was higher in all measurements with filled bladder compared with empty bladder, and during squeezing compared to the resting condition. All three drugs increased the opening urethral pressure during all four conditions with a ranking of their effect on urethral pressure matching their reported clinical effect (difference vs. placebo at their reported time of peak plasma concentrations [Tmax ] during resting with filled bladder: Midodrine 9.3 cmH2 O [95%CI 3.0, 15.5], Duloxetine 24.2 cmH2 O [95%CI 17.9, 30.5], and Reboxetine 44.9 cmH2 O [95% CI 40.2, 52.8] cmH2 O).
Urethral pressure reflectometry is capable of detecting drug-induced changes in urethral tone in various conditions. The magnitude of drug-induced changes by the test drugs seems to match their clinical profile and differences in mode of action.
Neurourology and urodynamics. 2017 Apr 18 [Epub ahead of print]
Niels Klarskov, Dirk Cerneus, William Sawyer, Donald Newgreen, Olivier van Till, Gunnar Lose
Department of Obstetrics and Gynecology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark., Astellas Pharma Europe BV, Leiden, The Netherlands.