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 mug)/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 (Cmin; Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24h) of ethinylestradiol/norethindrone (Day 15 Cycles 2 and 3) and rilpivirine (Day 15 Cycle 3) were evaluated. Results: Rilpivirine coadministration had no effect on (least square mean ratio 90% confidence interval) ethinylestradiol Cmin (1.09 1.03 - 1.16) or AUC24h (1.14 1.10 - 1.19) but increased Cmax by 17% (1.17 1.06 - 1.30) which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by rilpivirine (AUC24h: 0.89 0.84 - 0.94; Cmin: 0.99 0.90 - 1.08; Cmax: 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.