Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

摘要: In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m2. The highest peak plasma PCZ concentration achieved 1100 ng/ml. present study conducted to determine if levels high enough block doxorubicin (DOX) efflux in vitro could be and sustained vivo by increasing duration from 15 min 2 h. treatment schedule consisted prehydration with at least 500 ml normal saline (NS) administration fixed standard 60 mg/m2 DOX bolus over followed doses 75, 105, 135, or 180 250 NS hematologic toxicities attributable were expected independent dose. Toxicities sedation, dryness mouth, anxiety, akathisia, hypotension, cramps, confusion. MTD Large interpatient variation (91–3215 ng/ml) seen, half-life (t1/2α) being approximately 57 patients 135–180 PCZ. volume distribution (Vd), total clearance (ClT), area under curve (AUC) 350.1±183.8 l/m2, 260.7±142.7 l m2 h−1 1539±922 ng h−1, respectively, respective values for receiving 135 48.9±23.76 33.2±2.62 4117±302 h−1. High (>600 all treated up 24 elimination biphasic PCZ, a>10-ng/ml level maintained Partial responses seen three six malignant mesothelioma, two ten non-small-cell lung carcinoma, single patient hepatoma. Our data show can safely 2-h clinically manageable toxicities. antitumor activity combination needs confirmed II trials.