PHARMACOKINETICS OF DEXAMETHASONE AND VALSPODAR, A P-GLYCOPROTEIN (MDR1) MODULATOR - IMPLICATIONS FOR COADMINISTRATION

Study Objective. To assess the potential for a drug-drug interaction b etween valspodar, a P-glycoprotein (mdr1) modulator used as a chemothe rapy adjunct, and dexamethasone, widely included in oncology antiemeti c regimens. Design. Randomized, open-label, three-period crossover stu dy. 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 valsp odar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2- to 3-week washout phases between administrations. Measurements and Mai n Results. Lack of a pharmacokinetic drug-drug interaction with respec t to valspodar was conclusively demonstrated for both C-max,C-b (2.3 /- 0.4 vs 2.4 +/- 0.5 mu g/ml) and AUC(b) (19.8 +/- 4.8 vs 19.6 +/- 4. 9 mu g . hr/ml) inasmuch as bioequivalence criteria were satisfied whe n comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (C-max 88 +/- 23 vs 91 +/- 20 ng/m l), overall exposure was significantly increased by 24% on average (AU C 400 +/- 87 vs 494 +/- 90 ng . hr/ml). Regression analysis of valspod ar C-max,C-b and AUC(b) during coadministration versus the extent of t he interaction (percentage increase in dexamethasone AUG) did not reve al a concentration effect relationship (p=0.7299 and 0.9718, respectiv ely). Conclusion. Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clin ical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in de xamethasone's AUC is unlikely to be relevant. Thus no alterations in v alspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple-dose experience in patients would be desi rable to confirm these conclusions.