Pharmacokinetics of Two 6-Day Frovatriptan Dosing Regimens Used for the Short-Term Prevention of Menstrual Migraine

Abstract

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: 5mg; days 2–6: 2.5mg) and twice daily (day 1: 5mg [10mg total]; days 2–6: 2.5mg [5mg total]) in a randomized treatment sequence. Dosing was also random with respect to the menstrual cycle. Whole blood samples were obtained on days 1 and 6 (predose 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 1 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 (AUC₁₂) 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 0.8–1.7ng/mL) versus twice-daily frovatriptan (range 1.7–3.6ng/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.