A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.     

Preventive Ethics Through Expanding Education

Healthcare institutions have been making increasing efforts to standardize consultation methodology and to accredit both bioethics training programs and the consultants accordingly. The focus has traditionally been on the ethics consultation as the relevant unit of ethics intervention. Outcome measures are studied in relation to consultations, and the hidden assumption is that consultations are the preferred or best way to address day-to-day ethical dilemmas. Reflecting on the data from an internal quality improvement survey and the literature, we argue that having general ethics education as a key function of ethics services may be more important in meeting the contemporaneous needs of acute care settings. An expanded and varied ethics education, with attention to the time constraints of healthcare workers’ schedules, was a key recommendation brought forward by survey respondents. Promoting ethical reflection and creating a culture of ethics may serve to prevent ethical dilemmas or mitigate their effects.