Phase I Clinical Trial and Pharmacokinetic Evaluation of Acodazole (NSC 305884), an Imidazoquinoline Derivative with Electrophysiological Effects on the Heart

Acodazole (NSC 305844) is a synthetic imidazoquinoline which has antimicrobial as well as antineoplastic properties. A Phase I trial of acodazole administered as a 1-h i.v. infusion once weekly x 4 was conducted. Mild to moderate nausea and vomiting and moderate burning and erythema at the infusion site were the only toxicities seen among 33 patients treated over 51 courses at doses between 20 mg/m²/week and 888 mg/m². The first patient treated at 1184 mg/m² developed an irregular pulse and was found to have a prolonged cardiac output interval (Q-T₁) on electrocardiogram and polymorphic ventricular tachycardia (“torsades des pointes”). Careful study of five additional patients treated according to a modified schedule (340 mg/m² week one, 500 mg/m² week 2, 666 mg/m² week 3, and 888 mg/m² week 4) revealed 20% or greater Q-T₁ prolongation after 20 of 27 treatments; Q-T₁ prolongation had resolved 24–36 h after each infusion. Q-T₁ prolongation occurred at all dose levels; no ventricular arrhythmias occurred. Acodazole was cleared with a long t_1/2(20.7 h) primarily by nonrenal mechanisms. No alterations in peak plasma levels or excretion were seen in the patients in whom Q-T₁ prolongation was detected. No antitumor activity was seen. Further development of acodazole will require delineation of pharmacological means of surppressing this Q-T₁ prolongation.