The aim was to assess the pharmacokinetics of tolterodine released from vaginal rings and of its active metabolite 5-hydroxymethyl tolterodine (5-HMT) compared to the respective pharmacokinetics resulting from oral administration of extended-release tolterodine in healthy, postmenopausal women. In this single-center, open-label trial, subjects received 4 treatments in a fixed sequence: fasted oral extended-release tolterodine 2.74 mg/d (reference, 5 days), single vaginal rings; tolterodine releasing rates: 0.95 mg/d (test 1, 13 days), 1.40 mg/d (test 2, 28 days), 1.90 mg/d (test 3, 28 days). Systemic exposure of tolterodine, 5-HMT, and the molar sum of unbound tolterodine/5-HMT (active moiety [AM]) in steady state was determined. Sixteen of 18 included women completed the study. For the oral formulation, peak-trough fluctuations of tolterodine, 5-HMT, and AM plasma concentrations (AM: mean maximum/minimum concentration, 2580/574 pmol/L = 4.5) were large. Intravaginal application led to steadier plasma concentrations (AM, test 3: mean maximum/minimum concentration, 1880/814 pmol/L = 2.3; fluctuation due to initial peak), which is the result of constant releasing rates after ring insertion over the 28-day application period. The vaginal rings demonstrated a favorable local tolerability. The most common adverse events with oral and vaginal tolterodine were headache (n = 11) and dry mouth (n = 8). Vaginal rings releasing tolterodine represent a promising new formulation for overactive bladder treatment with little fluctuation of drug plasma levels. This is expected to lead to a more predictable and continuous therapeutic effect and a reduced frequency of side effects compared to oral tolterodine.
Keywords: 5-hydroxymethyl tolterodine; overactive bladder; pharmacokinetics; tolerability; tolterodine; vaginal ring.
© 2021, The American College of Clinical Pharmacology.