title: Assessment of disease-drug-drug interaction between single-dose tocilizumab and oral contraceptives in women with active rheumatoid arthritis.
abstract: OBJECTIVE
  The objective of this study was to evaluate the effect of a single intravenous dose of tocilizumab (TCZ) on pharmacokinetics (PK) of oral contraceptive (OC; norethindrone (NE) and ethinyl estradiol (EE)) and on sex hormone levels (progesterone (PG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)) in subjects with active rheumatoid arthritis (RA) who were on stable doses of methotrexate.
  
  
  METHODS
  This was an open-label, nonrandomized, multicenter, two-parallel group, one-sequence crossover study. In Group 1, Cycle 1 was a baseline cycle to determine the PK of OC and levels of sex hormones. At the start of Cycle 2, patients continued to receive OC and single TCZ dosing on Day 1. In Cycle 2, we determined the PK of OC and levels of sex hormones when OC and TCZ were combined. In Cycle 3, we determined the PK of OC and the levels of sex hormones after TCZ treatment was stopped. PK for EE and NE were analyzed serially on Day 7 when maximum TCZ effect on inflammation as indicated by C-reactiv protein (CRP) was expected. Hormone levels (PG, LH and FSH) were measured mid-cycle (cycle Days 12 - 16 and Day 21) during each cycle. Group 2 (healthy subjects) was studied to compare the levels of OC PK exposures with those in each cycle of Group 1 (RA subjects).
  
  
  RESULTS
  Levels of PG, LH and FSH were not affected by the combination of TCZ/OC treatment in RA patients studied. No breakthrough bleeding was attributed to the initiation of TCZ treatment in subjects receiving OCs. PK exposures of EE and NE were similar between RA and healthy subjects at baseline and were not affected by single-dose TCZ. Administration of OC with or without a single dose of TCZ was well tolerated.
  
  
  CONCLUSIONS
  Data from this study indicated that the PK and sex hormone levels were not affected in RA subjects who had active disease and were on a stable regimen of methotrexate.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Lucy
authors.initials: L
authors.lastname: Rowell
authors.forename: Scott
authors.initials: S
authors.lastname: Fettner
authors.forename: Carol
authors.initials: C
authors.lastname: Lau
authors.forename: Denise
authors.initials: D
authors.lastname: Teuber
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002097:C-Reactive Protein / Q000032:analysis; D003276:Contraceptives, Oral / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D009640:Norethindrone / Q000493:pharmacokinetics*; D011374:Progesterone / Q000097:blood; D019947:Receptors, Interleukin-6 / Q000097:blood
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003276:Contraceptives, Oral; D019947:Receptors, Interleukin-6; D004997:Ethinyl Estradiol; D011374:Progesterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002097:C-Reactive Protein; C502936:tocilizumab; D009640:Norethindrone