P‐Glycoprotein and Breast Cancer Resistance Protein Transporter Inhibition by Cyclosporine and Quinidine on the Pharmacokinetics of Oral Rimegepant in Healthy Subjects

Abstract

Rimegepant (Nurtec ODT)—an orally administered, small‐molecule calcitonin gene–related peptide receptor antagonist indicated for the acute and preventive treatment of migraine—is a substrate for both the P‐glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single‐center, open‐label, randomized study was conducted in 2 parts, both of which were 2‐period, 2‐sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200‐mg cyclosporine, a strong inhibitor of the P‐glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600‐mg quinidine, a strong selective P‐glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49‐1.72) and 1.41 (1.27‐1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40‐1.72) and 1.67 (1.46‐1.91), respectively, versus rimegepant alone. Strong P‐glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2‐fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure.

Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants

“…Rimegepant has a half-life of 7 to 8.5 h in healthy participants, while mean half-lives range between 10 and 17 h for EE and 18 and 25 h for NGMN. 19,22,24 In general assumptions, steady-state concentration is achieved after administering medication to healthy participants for approximately five half-lives. 25 Therefore, EE and NGMN reached steady state by day 7 in cycle 2, and rimegepant reached steady state by day 14 in cycle 2 after its administration was started on day 12.…”

“…Rimegepant, EE, and NGMN reached steady state before the analysis for pharmacokinetic parameters was performed after co‐administration of multiple doses of rimegepant (day 19). Rimegepant has a half‐life of 7 to 8.5 h in healthy participants, while mean half‐lives range between 10 and 17 h for EE and 18 and 25 h for NGMN 19,22,24 . In general assumptions, steady‐state concentration is achieved after administering medication to healthy participants for approximately five half‐lives 25 .…”

“…Overall, a strong CYP3A4 inhibitor may increase the exposure of rimegepant, but a weak CYP3A4 should not have a clinically significant impact on rimegepant exposure. 13,19 In the United States, approximately 14% of females of childbearing age use an oral contraceptive. 20 Most oral contraceptives contain two components-an estrogen and a progestin.…”

“…The primary metabolism of rimegepant occurs via CYP3A4 and, to a lesser extent, via CYP2C9. Overall, a strong CYP3A4 inhibitor may increase the exposure of rimegepant, but a weak CYP3A4 should not have a clinically significant impact on rimegepant exposure 13,19 …”

Influence of Rutin and Quinidine on Absorbable Sutures

“…The length of the action potential is lengthened by the medication. (11) In numerous foods, including buckwheat, apricots, cherries, grapes, grapefruit, plums, and oranges, rutin is a naturally occurring flavonoid. Patients with capillary fragility, varicose veins, bruises, or hemorrhoids frequently utilize it.…”