2.3 Treatments In accordance with a two-way randomized crossover study design, participants were given two 5-day treatments (days 1–5 of each crossover phase; Fig. 1) with a once-daily oral contraceptive, once as monotherapy (treatment A) and once with once-daily prucalopride on days 1–6 of the treatment phase (treatment B). The washout
period between the two contraceptive treatments was 7 ± 2 days. The stage of the patient’s menstrual cycle was not taken into account in the timings of these treatments. The oral contraceptive Trinovum® (ethinylestradiol 0.035 mg and norethisterone 1 mg; Janssen-Cilag Ltd) was used; prucalopride was administered as 2 mg film-coated tablets containing prucalopride Doramapimod mouse succinate, equivalent to 2.0 mg prucalopride base. Fig. 1 Overview of the trial design. OC oral contraceptive The oral contraceptive dose was taken at 0800 hours. For the combination treatment, prucalopride was administered immediately before the oral contraceptive. The drugs were taken with a total of 200 mL of non-carbonated
water. On days 1 and 5 of each treatment period, the study medication was administered in the clinic following an overnight fast of at least 10 hours, and participants were not permitted to eat or drink until 2 hours TPX-0005 concentration after receiving the medication, at which time they received a standard breakfast. On all other days, participants took the study treatments either
at the clinic (days 2 and 6) or at home (days 3 and 4) 30 minutes before breakfast. Compliance was LBH589 purchase assessed by investigator supervision of dosing (except on days 3 and 4) and daily diary entries. During the study, participants were not permitted to take medication other than the study drugs, with the exception of as-needed Selleck Gefitinib paracetamol/acetaminophen (up to a maximum of three 500 mg tablets per day, and no more than 3 g during the study). 2.4 Pharmacokinetic Assessments Serial blood samples for the determination of ethinylestradiol and norethisterone concentrations in plasma were taken on day 1 pre-dose and then at 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose, and on day 5 pre-dose and then at 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours post-dose. Participants receiving treatment B had serial blood samples collected for the determination of plasma concentrations of prucalopride on days 1 and 5 pre-dose and then at 3 hours post-dose, and on day 6 pre-dose and then at 24 hours post-dose. No pharmacokinetic parameters were calculated for prucalopride. 2.4.1 Assay Validation Plasma samples were analyzed for prucalopride, ethinylestradiol, and norethisterone, using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods.
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