Phase I and Pharmacological Study of the Novel Topoisomerase I Inhibitor 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) Administered as a Ninety-Minute Infusion Every 3 Weeks

摘要: 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan), a semisynthetic analogue of camptothecin (CPT) with broad preclinical antitumor activity, has demonstrated impressive activity in phase II trials Japan advanced small and non-small cell lung, colorectal, cervical, ovarian carcinomas, as well refractory lymphomas leukemias. In this I pharmacological study, 90-min infusions CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m2 patients solid malignancies. Acute, severe, vomiting, diarrhea, and/or abdominal cramps associated flushing, warmth, diaphoresis occurred the immediate posttreatment period 240-mg/m2 dose level several who not treated premedications. The characteristics temporal nature these toxicities, prompt resolution symptoms following treatment diphenhydramine, successful use premedication regimen consisting ondansetron diphenhydramine preventing acute effects suggest that vasoactive substances are involved mediation toxicities. With routine premedications, there was no single toxicity type limited escalation doses. Instead, constellation severe hematological gastrointestinal precluded repetitive administration above 240 mg/m2, maximum tolerated recommended on schedule. Major responses observed renal cancers. disposition total plasma fit by biexponential kinetic model elimination accounting for 37 +/- 4% (SE) drug disposition. Cmax active metabolite CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), achieved 2.2 0.1 h after treatment, mean residence times both SN-38 long, 9.1 10.0 h, respectively. Compared topotecan, another CPT under development, larger proportion exposure accounted lactone (closed-ring) forms SN-38; areas time-versus concentration curve their respective 44 50% time-versus-concentration SN-38. Although intermittent dosing schedules appear be superior some analogues tumor models, maintenance biologically relevant concentrations relatively long durations may negate potential benefits continuous CPT-11.(ABSTRACT TRUNCATED AT 400 WORDS)