Preclinical pharmacokinetic and tolerance assessment and phase I clinical trial of MU-Gold, a novel chemotherapeutic agent.

摘要

MU-Gold, [Au(THP4)]Cl, a novel gold compound, has been proposed to inhibit cell growth via G1 cell cycle phase elongation. Canine lymphoma is a chemosensitive neoplasm comparable to human non-Hodgkin's lymphoma. The dog is a suitable model for evaluation of antitumor activity and for assessment of pharmacokinetics of novel drugs.; Three purpose-bred dogs were obtained and MU-Gold (10 mg/kg IV) was administered. Serum was collected for gold measurement via atomic absorption spectrometry at 21 time points over 72 hours post-injection. Pharmacokinetics best fit a 2-compartment IV bolus model with first order kinetics. Mean elimination half-life was 40 hours and mean volume of distribution was 0.6 L/kg.; A Phase I clinical trial was performed in lymphoma-bearing dogs. A dose escalation study was conducted with three dogs enrolled at three doses (10 mg/kg, 25 mg/kg and 50 mg/kg). MU-Gold was administered IV every three weeks for four treatments. The final dog received 37.5 mg/kg rather than 50 mg/kg due to toxicity. Serum gold levels achieved correlated with those achieved in normal dogs. The maximally tolerable dose of MU-Gold evaluated was 25 mg/kg and the dose limiting toxicity was thrombocytopenia.