Pharmacokinetic Interaction Between the MEK1/MEK2 Inhibitor Trametinib and Oral Contraceptives Containing Norethindrone and Ethinyl Estradiol in Female Patients With Solid Tumors.

Abstract

This phase 1 postapproval study assessed the effect of the mitogen-activated protein kinase kinase enzyme 1/enzyme 2 inhibitor trametinib (2 mg once daily, repeat dosing) on the pharmacokinetics of combined oral contraceptives (COCs) containing norethindrone (NE; 1 mg daily) and ethinyl estradiol (EE; 0.035 mg daily) in 19 female patients with solid tumors. Compared with NE/EE administered without trametinib, NE/EE administered with steady-state trametinib was associated with a clinically nonrelevant 20% increase in NE exposure (area under the curve [AUC]) and no effect on EE exposure (geometric mean ratio [geo-mean] of NE/EE + trametinib to NE/EE [90%CI]: NE AUC calculated to the end of a dosing interval at steady-state [AUCtau ] 1.20 [1.02-1.41]; NE AUC from time zero to the last measurable concentration sampling time [AUClast ] 1.2 [0.999-1.45]; EE AUCtau 1.06 [0.923-1.22]; EE AUClast 1.05 [0.883-1.25]). Maximum serum concentration (Cmax ) of NE increased by 13% and Cmax of EE decreased by 8.5% when dosed with steady-state trametinib compared with COCs administered alone (geo-mean ratio [90%CI]: NE Cmax 1.13 [0.933-1.36]; EE Cmax 0.915 [0.803-1.04]). These results indicate that repeat-dose trametinib does not lower exposure to NE or EE and, hence, is unlikely to impact the contraceptive efficacy of COCs. The pharmacokinetic parameters of trametinib and its metabolite M5 were consistent with historic data of trametinib alone. Coadministration of trametinib and COCs was generally well tolerated in this study, with observed safety signals consistent with the known safety profile of trametinib and no new reported safety events. Overall, the findings indicate that hormonal COCs can be coadministered in female patients who receive trametinib monotherapy without compromising the contraceptive efficacy.