PHASE-I AND PHARMACOKINETIC STUDY OF INTRAPERITONEAL TOPOTECAN

Objective. To determine the maximum tolerated dose and pharmacokinetic s of topotecan when administered by the intraperitoneal route, Methods . A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusi on over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. Results. Se venteen patients received a total of 43 cycles at 21-day intervals. Th e maximum tolerated dose was 4 mg/m(2) and acute dose-limiting toxicit y was neutropenia. Other toxicities included leukopenia, anemia, emesi s, fever, and abdominal pain. Although no objective responses were ach ieved, five of patients with ascites had a decrease in fluid accumulat ion with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m(2). Pharmacokinetic analysis performed at a do se of 3 mg/m(2) demonstrated that elimination from the peritoneal cavi ty followed second-order kinetics with k(1) = 1.6 hr(-1), k(2) = 0.3 h r(-1) and first and second-phase half-lives of 0.49 and 2.7 hours, res pectively. Plasma pharmacokinetic behavior was best described by first -order kinetics with k = 0.5 hr(-1) and a half-life of 3.9 hours, The pharmacologic advantage, expressed as the peritoneal to plasma AUC rat io was 31.2. Conclusions. Intraperitoneal administration of topotecan at 3 mg/m(2) results in a substantial increase in drug exposure for th e peritoneal cavity without compromising systemic exposure; this may b e beneficial for the treatment of patients with ovarian cancer or intr aperitoneal carcinomatosis.