Pharmacokinetics of Two 6-Day Frovatriptan Dosing Regimens Used for the Short-Term Prevention of Menstrual Migraine A Phase I. Randomized, Double-Blind, Placebo-Controlled, Two-Period Crossover, Single-Centre Study in Healthy Female Volunteers

Objective: This study aimed to assess the pharmacokinetics and tolerability of once- and twice-daily frovatriptan given for 6 days, a regimen that has previously been reported to reduce the incidence and severity of menstrual migraine when administered during the perimenstrual period. Methods: This was a double-blind, placebo-controlled, two-period crossover study carried out in healthy premenopausal female volunteers aged >= 18 years (equal number taking or not taking estrogen-containing contraceptives [ECCs]) who were admitted to a clinical pharmacology unit. Women alternately received frovatriptan once daily (day 1: 5 mg; days 2-6: 2.5 mg) and twice daily (day 1: 5 mg [10 mg total]; days 2-6: 2.5 mg [5 mg total]) in a randomized treatment sequence. Dosing was also random with respect to the menstrual cycle. Whole blood samples were obtained on days I and 6 (pre-dose and at 0.5, 1, 2, 4, 6, 8, 12 [before evening dose], 13, 14, 16 and 18 hours post-dose) and on days 2-5 (samples were taken before the morning dose). A final sample was drawn at 24 hours after the last treatment on day 6. A fully validated liquid chromatography assay coupled to a tandem mass spectroscopy assay measured drug concentrations (simultaneous measurement of frovatriptan and its metabolites). Pharmacokinetic parameters were determined using a noncompartmental approach. Safety and tolerability were measured by monitoring adverse events, haematology and biochemistry, vital signs, ECG results and physical examination findings. Results: Twenty-six healthy women participated in the study and 24 (12 ECC users and 12 ECC nonusers) completed the study. One ECC user during period I and one nonuser during period 2 withdrew before completion; both were taking frovatriptan once daily. Most women were White (n = 21), three were Black, and one each was Hispanic or Asian; mean +/- SD age was 25.4 +/- 4.9 years; and mean +/- SD weight was 61.9 +/- 6.5 kg. For both once- and twice-daily dosing, time to reach maximum blood concentration (C-max) [t(max)] was in the range of 2-4 hours. The loading dose enabled steady state (defined as constant trough blood concentration [C-min]) to be reached by day 2 with both regimens. Geometric mean C-max and area under the blood concentration-time curve from 0 to 12 hours (AUC(12)) were higher with twice- versus once-daily dosing (day 1: p < 0.02; day 6: p < 0.001 for both). C-min was lower with once- (range 0.8-1.7 ng/mL) versus twice-daily frovatriptan (range 1.7-3.6 ng/mL). The ratio of C-max: C-min on days 1 and 6 was lower with twice- than with once-daily dosing, indicating less fluctuation in frovatriptan blood concentrations. ECC users had 26-68% higher C-max and AUC from 0 to 24 hours values than nonusers on days 1 and 6 (p < 0.02); the clinical relevance of this is not known. Both dosing regimens were well tolerated; one incident of vomiting and one of headache were rated as moderate, with all other adverse events being rated as mild. Conclusion: Both frovatriptan regimens achieved steady-state therapeutic blood concentrations by day 2. Twice-daily dosing maintained more consistent drug concentrations than once-daily dosing and was well tolerated.