title: Lack of an effect of rilpivirine on the pharmacokinetics of ethinylestradiol and norethindrone in healthy volunteers.
abstract: 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 μg)/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.
authors.forename: Herta M
authors.initials: HM
authors.lastname: Crauwels
authors.forename: Rolf P G
authors.initials: RP
authors.lastname: van Heeswijk
authors.forename: Annemie
authors.initials: A
authors.lastname: Buelens
authors.forename: Marita
authors.initials: M
authors.lastname: Stevens
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D019540:Area Under Curve; D003278:Contraceptives, Oral, Hormonal / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D009570:Nitriles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D009640:Norethindrone / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068696:Rilpivirine
chemical_list: D019380:Anti-HIV Agents; D003278:Contraceptives, Oral, Hormonal; D004338:Drug Combinations; D009570:Nitriles; D011743:Pyrimidines; C020416:norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination; D004997:Ethinyl Estradiol; D000068696:Rilpivirine; D009640:Norethindrone