Objective: The current study was designed to investigate
pharmacokinetic profiles and to observe the human tolerance to
10 hydroxycamptothecin in the patients with advanced malignancy. Methods: HCPT is an topoisomerase Ⅰ inhibitor, obtained from Chinese tree Camptotheca acumineta. Its dose initiated at 5 mg/m2, was solved in 0.9%normal saline(NS) 100 ml and given as a 30 min infusion at constant speed for 5 consecutive days, then escalated to 7.5 mg/m2, 12 mg/m2, 16 mg/m2,and 20 mg/m2,respectively. The patients were evaluated for response and toxicity after two weeks. Heparinized blood samples(2 ml) were collected on the first infusion day, immediately predose (time 0), then postinfusion at 0, 15, 30 minutes, and 2, 4, 6, 8, 12 hours. Pharmacokinetics was evaluated by high performance liquid chromatography (HPLC). Results: Twenty four patients suitable for phase Ⅰ eligibility criteria were included (6 women,18 men; median age 52.61 years). The main toxicities were
myelosuppression and diarrhea, and encounted at median and high doses level. Other toxcities involved Ⅰ-Ⅱ nausea/voimting, hepatic function disorder, hematuria,and exanthem. Pharmacokinetics was performed in 24 patients. HCPT plasma concentration was biphasic, with distribution half life and terminal elimination half life of 0.0523h-0.613h and 1.03h-2.42h respectively. Distribution volumes was 5.54-11.4L/m2. HCPT area under the plasma concentration versus time (AUC) and maximum concentration (Cmax) increased linearly with dose escalating. About 10-20% of the total HCPT circulating in plasma was in the lactone form. The rate of protein bound is 65%-99% Twenty four hour urinary excretion accounted for 24%of the dose. Conclusion: The dose limiting toxicities of HCPT in human were myelosuppression and diarrhea. morbidity and degree increased according with dose from 5 mg/m2 to 20 mg/m2. Toxicity was reversible and manageable. The maximum tolerance dosage (MTD) is 16 mg/m2, and the recommendation dose is 12 mg/m2. Carboxylate HCPT was the main form existing in plasma and HCPT plasma concentration was biphasic.