0 [1.0–2.0] 1.0 [1.0–2.0] 0.00 −0.50, 0.00 0.6000  Cmin (ng/mL) 0.97 ± 0.45 1.00 ± 0.44 97.94 84.37, 113.70 0.8059  Cmax (ng/mL) 17.0 ± 4.8 17.1 ± 4.9 99.00 88.02, 111.35 0.8801  AUCτ (ng·h/mL) 100 ± 37 100 ± 35 96.04 88.28, 104.47 0.4045  t½ (h) Pexidartinib purchase 10.3 ± 2.0 9.9 ± 1.9 – – 0.1637 aValues are expressed as means ± standard deviations, except for tmax, for which median [range] values are given bResults are based on all data (n = 13) and on n = 12 after exclusion of one participant because circumstantial evidence indicated that her medication was not taken on days 3 and/or 4 AUC τ area under the plasma concentration–time curve during a 24-hour dosing interval, AUC 24 area

under the plasma concentration–time curve during PLX4032 molecular weight the first 24-hour dosing interval, CI confidence interval, C max maximum plasma concentration, C min minimum plasma concentration, OC oral contraceptive, PE point estimate of the geometric mean treatment ratio, t ½ elimination half-life, t max time to reach Cmax Norethisterone steady state was reached on day 5, with plasma concentrations of norethisterone being similar before and 24 hours after administration of oral contraceptive alone (0.97 ± 0.47 ng/mL

and 1.13 ± 0.51 ng/mL, respectively) and oral contraceptive plus prucalopride (0.92 ± 0.51 ng/mL and 1.11 ± 0.48 ng/mL, respectively) [Fig. 3]. On day 5, Cmax was reached at a median time of 1 hour after dosing. There were no statistically significant differences in tmax, Cmin, Cmax, AUCτ, or t½ between treatments (Table 2). The geometric mean treatment ratios for Cmax and AUCτ were 98.07 % and 91.36 %, acetylcholine respectively, and the associated 90 % CIs were within the predefined equivalence limits of 80–125 % for Cmax and AUCτ (Table 2). For Cmin, the geometric mean treatment ratio and the lower limit of the 90 % CI were below 80 % when all participants were included in the analysis. However, these parameters fell within the predefined equivalence limits when the data from the suspected non-compliant participant were omitted (Table 2). 3.4 Prucalopride Pharmacokinetics On day 1, the mean near-peak (3-hour) concentration of prucalopride was 4.56 ± 0.87 ng/mL. On day

5, prucalopride steady state was reached, with similar plasma concentrations pre-dose on days 5 and 6 and at 24 hours post-dose on day 6 (3.00 ± 1.16 ng/mL, 3.20 ± 0.84 ng/mL, and 3.13 ± 0.58 ng/mL, respectively). On day 5, the mean near-peak (3-hour) EPZ015938 clinical trial steady-state plasma concentration of prucalopride was 8.18 ± 1.64 ng/mL. 3.5 Prucalopride Safety and Tolerability No unexpected safety findings for prucalopride were identified on administration with ethinylestradiol and norethisterone. No deaths or serious or severe treatment-emergent AEs were reported. Treatment-emergent AEs were more common in participants receiving prucalopride plus oral contraceptive (39 events, n = 15 [93.8 %]) than in those receiving oral contraceptive alone (4 events, n = 4 [30.8 %]).