Lack Of An Effect Of Rilpivirine On The Pharmacokinetics Of Ethinylestradiol And Norethindrone In Healthy Volunteers

Rilpivirine is a human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor. Objective: Rilpivirine metabolism involves cytochrome P450 3A4 (CYP3A4). This trial (ClinicalTrials.gov number: NCT00739622) evaluated the interaction between rilpivirine and ethinylestradiol/norethindrone (combination oral contraceptives), which are metabolized by multiple pathways, including CYP3A4. Methods: During three consecutive 28-day cycles, 18 HIV-negative females received once-daily ethinylestradiol (35 mu g)/norethindrone (1 mg) (days 1 - 21); days 22 - 28 were pill-free. Only in cycle 3 was once-daily rilpivirine (25 mg) co-administered (days 1 - 15). Minimum and maximum plasma concentrations (C-min; C-max) and area under the plasma concentration-time curve over 24 hours (AUC(24h)) of ethinylestradiol/norethindrone (day 15, cycles 2 and 3) and rilpivirine (day 15, cycle 3) were evaluated. Results: Rilpivirine co-administration had no effect on (least square mean ratio, 90% confidence interval) ethinylestradiol C-min (1.09, 1.03 - 1.16) or AUC(24h) (1.14, 1.10 - 1.19), but increased C-max by 17% (1.17, 1.06 - 1.30), which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by rilpivirine (AUC(24h): 0.89, 0.84 - 0.94; C-min: 0.99, 0.90 - 1.08; C-max : 0.94, 0.83 - 1.06). Steady-state rilpivirine pharmacokinetics with ethinylestradiol/norethindrone was comparable with historical data for rilpivirine alone. Rilpivirine with ethinylestradiol/norethindrone was generally well tolerated. No new safety events were identified. Conclusions: Co-administration of rilpivirine, at the therapeutic dosing regimen, with ethinylestradiol/norethindrone does not affect hormone pharmacokinetics, and is, therefore, unlikely to affect the efficacy or safety of this oral hormonal contraceptive. Rilpivirine pharmacokinetics was not affected by ethinylestradiol/norethindrone. Rilpivirine (25 mg once daily) can be co-administered with ethinylestradiol/norethindrone-based contraceptives without dose modification.