Pharmacokinetics of dexamethasone and valspodar, a P-glycoprotein (mdr1) modulator: implications for coadministration.
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.
Kovarik
J M
JM
Department of Clinical Pharmacology, Novartis Pharma AG, Basel, Switzerland.
Purba
H S
HS
Pongowski
M
M
Gerbeau
C
C
Humbert
H
H
Mueller
E A
EA
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000932:Antiemetics; D003524:Cyclosporins; D003907:Dexamethasone; C070272:valspodar