Pharmacokinetics of dexamethasone and valspodar, a P-glycoprotein (mdr1) modulator: implications for coadministration.
Pharmacotherapy
; 18(6): 1230-6, 1998.
Article
em En
| MEDLINE
| ID: mdl-9855321
ABSTRACT
STUDY 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.DESIGN:
Randomized, open-label, three-period crossover study.SETTING:
Clinical pharmacology research center.SUBJECTS:
Eighteen healthy men volunteers (age 25.8+/-3.5 yrs, weight 71.6+/-10.3 kg).INTERVENTIONS:
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. MEASUREMENTS AND MAINRESULTS:
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).CONCLUSION:
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.
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Base de dados:
MEDLINE
Assunto principal:
Dexametasona
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Ciclosporinas
/
Antieméticos
Idioma:
En
Ano de publicação:
1998
Tipo de documento:
Article