Pharmacokinetics of Dexamethasone and Valspodar, a P‐glycoprotein ( mdr1 ) Modulator: Implications for Coadministration

Study Objective . To assess the potential for a drug‐drug interaction between valspodar, a P‐glycoprotein ( mdr1 ) 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 Main Results . Lack of a pharmacokinetic drug‐drug interaction with respect to valspodar was conclusively demonstrated for both C max,b (2.3 ± 0.4 vs 2.4 ± 0.5 μg/ml) and AUC b (19.8 ± 4.8 vs 19.6 ± 4.9 μg·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 (C max 88 ± 23 vs 91 ± 20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400 ± 87 vs 494 ± 90 ng·hr/ml). Regression analysis of valspodar C max,b and AUC b 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.