PHARMACOKINETIC PROFILE OF MITOGUAZONE (MGBG) IN PATIENTS WITH AIDS-RELATED NON-HODGKINS-LYMPHOMA

Mitoguazone is a unique chemotherapeutic agent whose activity is belie ved to result primarily from the competitive inhibition of S-adenosyl- methionine decarboxylase leading to a disruption in polyamine biosynth esis. Initial clinical trials demonstrated that the dose-limiting toxi cities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone i n man revealed a prolonged half-life. Concurrent with a recent Phase I I trial of Mitoguazone in patients with AIDS related non-Hodgkin's lym phoma, the single dose pharmacokinetics of Mitoguazone were characteri zed. Twelve patients received 600 mg/m(2) of intravenous Mitoguazone o ver 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were coll ected and analyzed by HPLC. Mitoguazone was cleared from the plasma tr iexponentially with a harmonic mean terminal half-life of 175 hours an d a mean residence time of 192 hours. Peak plasma levels occurred imme diately post-infusion, ranged from 6.47 to 42.8 mu g/ml, and remained (for an extended period) well above the reported concentration for inh ibition of polyamine biosynthesis. Plasma clearance averaged 4.73 1/hr /m(2) with a relatively large apparent volume of distribution at stead y-state of 1012 l/m(2) indicating tissue sequestration. Renal excretio n of unchanged Mitoguazone accounted for an average of 15.8% of the do se within 48 to 72 hours post-administration. Detectable levels of dru g were present in random voided samples eight days post-dose. Mitoguaz one levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasm a ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was a pproximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.