title: NCT01110291: induction of CYP3A activity and lowered exposure to docetaxel in patients with primary breast cancer.
abstract: OBJECTIVE
  To study the CYP3A activity before and after docetaxel administration. Furthermore, it was investigated whether peroral midazolam could predict docetaxel exposure and adverse events.
  
  
  METHODS
  Twenty patients with primary high risk breast cancer were given docetaxel as a 1-h infusion 80 mg/m(2) in a 21-day cycle in 3 cycles followed by 3 cycles of cyclophosphamide, epirubicin and fluorouracil. CYP3A activity was assessed a day before and a day after docetaxel by 7.5 mg oral midazolam. All patients were given peroral dexamethasone a total dose of 45 mg, of which 15 mg was given before docetaxel infusion and 30 mg before the latter assessment of CYP3A activity. All except one patient were given 11-19 mg of intravenous dexamethasone before docetaxel infusion.
  
  
  RESULTS
  CYP3A activity was clearly induced when assessed a day after docetaxel administration as shown by lower midazolam AUC (P < 0.0001) and higher AUC ratio (1-OH-midazolam/midazolam, P = 0.018). The mean docetaxel AUC was about a half of that previously reported in the literature. Incidence of febrile neutropenia was smaller (15%) than reported in literature with comparable docetaxel doses and seemed to associate with slower metabolism. No correlation between pharmacokinetics of midazolam and docetaxel was found at baseline.
  
  
  CONCLUSIONS
  We show here a markedly reduced docetaxel exposure followed by CYP3A induction by, most likely, dexamethasone. Peroral midazolam seemed not to predict docetaxel exposure. Slow CYP3A-mediated metabolism might predispose patients to adverse events of docetaxel.
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4B, 3rd floor, 20520 Turku, Finland. johanna.hilli@utu.fi
authors.forename: Johanna
authors.initials: J
authors.lastname: Hilli
authors.forename: Liisa
authors.initials: L
authors.lastname: Sailas
authors.forename: Sirkku
authors.initials: S
authors.lastname: Jyrkkiö
authors.forename: Seppo
authors.initials: S
authors.lastname: Pyrhönen
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D000077143:Docetaxel; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood; D008875:Middle Aged; D016019:Survival Analysis; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D043823:Taxoids; D000077143:Docetaxel; D003907:Dexamethasone; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam