PHASE-I AND PHARMACOKINETICS STUDIES OF PROCHLORPERAZINE-2-H IV-INFUSION AS A DOXORUBICIN-EFFLUX BLOCKER

In an earlier phase I study, we reported that the maximal tolerated do se (MTD) of prochlorperazine (PCZ) given as a 15-min i, v. infusion wa s 75 mg/m(2). The highest peak plasma PCZ concentration achieved was 1 100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achiev ed and sustained in vivo by increasing the duration of i.v. infusion f rom 15 min to 2 h. The treatment schedule consisted of i.v. prehydrati on with at least 500 ml normal saline (NS) and administration of a fix ed standard dose of 60 mg/m(2) DOX as an i.v. bolus over 15 min follow ed by i.v. doses of 75, 105, 135, or 180 mg/m(2) PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were s edation, dryness of mouth, anxiety, akathisia, hypotension, cramps, an d confusion. The MTD of PCZ was 180 mg/m(2). Large interpatient variat ion in peak PCZ plasma levels (91-3215 ng/ml) was seen, with the plasm a half-life (t(1/2 alpha)) being approximately 57 min in patients give n 135-180 mg/ m(2) PCZ. The volume of distribution (V-d), total cleara nce (Cl-T), and area under the curve (AUC) were 350.1+/-183.8 l/m(2), 260.7+/-142.7 1 m(2) h(-1) and 1539+/-922 ng ml h(-1), respectively, i n patients given 180 mg/m(2) PCZ and the respective values for patient s receiving 135 mg/m(2) were 48.9+/-23.76 l/m(2), 33.2+/-2.62 1 m(2) h (-1) and 4117+/-302 ng ml h(-1). High PCZ plasma levels (> 600 ng/ml) were sustained in all patients treated with 135 mg/m(2) PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m(2) PCZ, and a > 10-ng/ml DOX plasma level was maintained for 24 h. Partial res ponses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely gi ven as a 2-h infusion at 135 mg/m(2) with clinically manageable toxici ties. The antitumor activity of the combination of DOX and PCZ needs t o be confirmed in phase II trials.