title: Pharmacokinetics of dexamethasone and valspodar, a P-glycoprotein (mdr1) modulator: implications for coadministration.
abstract: OBJECTIVE
  To assess the potential for a drug-drug interaction between valspodar, a P-glycoprotein (mdrl) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens.
  
  
  METHODS
  Randomized, open-label, three-period crossover study.
  
  
  METHODS
  Clinical pharmacology research center.
  
  
  METHODS
  Eighteen healthy men volunteers (age 25.8+/-3.5 yrs, weight 71.6+/-10.3 kg).
  
  
  METHODS
  Subjects received single fasting oral doses of valspodar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2- to 3-week washout phases between administrations.
  
  
  RESULTS
  Lack of a pharmacokinetic drug-drug interaction with respect to valspodar was conclusively demonstrated for both Cmax,b (2.3+/-0.4 vs 2.4+/-0.5 microg/ml) and AUCb (19.8+/-4.8 vs 19.6+/-4.9 microg x hr/ml) inasmuch as bioequivalence criteria were satisfied when comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (Cmax 88+/-23 vs 91+/-20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400+/-87 vs 494+/-90 ng x hr/ml). Regression analysis of valspodar Cmax,b and AUCb during coadministration versus the extent of the interaction (percentage increase in dexamethasone AUC) did not reveal a concentration-effect relationship (p=0.7299 and 0.9718, respectively).
  
  
  CONCLUSIONS
  Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clinical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in dexamethasone's AUC is unlikely to be relevant. Thus no alterations in valspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple-dose experience in patients would be desirable to confirm these conclusions.
authors.affiliation: Department of Clinical Pharmacology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: J M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: H S
authors.initials: HS
authors.lastname: Purba
authors.forename: M
authors.initials: M
authors.lastname: Pongowski
authors.forename: C
authors.initials: C
authors.lastname: Gerbeau
authors.forename: H
authors.initials: H
authors.lastname: Humbert
authors.forename: E A
authors.initials: EA
authors.lastname: Mueller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000328:Adult; D000932:Antiemetics / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D003524:Cyclosporins / Q000009:adverse effects / Q000493:pharmacokinetics*; D003907:Dexamethasone / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005121:Extremities; D006801:Humans; D016014:Linear Models; D008297:Male; D010292:Paresthesia / Q000139:chemically induced
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000932:Antiemetics; D003524:Cyclosporins; D003907:Dexamethasone; C070272:valspodar