ISSN:
1569-8041
Keywords:
BBR3464
;
phase I
;
platinum analog
;
pharmacokinetics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Objectives:To define the maximum tolerated dose (MTD), thetoxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods:Fourteen patients with advanced solid tumorsnot responsive to previous antitumor treatments received BBR 3464 on a daily× 5 schedule every twenty-eighth day. The drug was given as a one-hourinfusion with pre-and post-treatment hydration (500 ml in one hour) and noantiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. Amodified accelerated titration escalation design was used. Total and freeplatinum (Pt) concentrations in plasma and urine were assessed by ICP-MS ondays 1 and 5 of the first cycle. Results:Dose was escalated four times up to 0.17mg/m2/day. Short-lasting neutropenia and diarrhea of late onsetwere dose-limiting and defined the MTD at 0.12 mg/m2. Nausea andvomiting were rare, neither neuro- nor renal toxic effects were observed.BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-lifeof several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 werehigher than on day 1, indicating drug accumulation. Approximately 10%of the equivalent dose of BBR3464 (2.2%–13.4%) wasrecovered in a 24-hour urine collection. Conclusions:The higher than expected incidence of neutropenia andGI toxicity might be related to the prolonged half-life and accumulation oftotal and free Pt after daily administrations. Lack of nephrotoxicity and thelow urinary excretion support the use of the drug without hydration. Thesingle intermittent schedule has been selected for clinical development.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008302309734
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