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摘要
9-Nitrocamptothecin (9-NC) is a novel orally administered camptothecin analog. The purpose of this study is to evaluate the pharmacokinetics and safety of 9-nitrocamptothecin in patients with advanced solid tumors. @@@ The 23 patients for a single-dose pharmacokinetic experiment were divided into 3 dosing cohorts. The dosage of 9-nitrocamptothecin capsule was 1.25, 1.5 and 1.75 mg/m(2), respectively. The 8 patients for a multiple-dose pharmacokinetic study were orally administered 9-nitrocamptothecin 1.5 mg/m(2) for 5 consecutive days. Determination of the plasma concentration of 9-nitrocamptothecin was performed by high-performance liquid chromatography-ultraviolet detector technique, and determination of plasma concentration of 9-aminocamptothecin was performed by high-performance liquid chromatography-fluorescence detector technique. @@@ In the single-dose pharmacokinetic study, the mean +/- A SD 9-nitrocamptothecin C (max) were 94.49 +/- A 41.38, 115.56 +/- A 63.27 and 147.57 +/- A 38.19 ng/mL; AUC(0-36) were 877.14 +/- A 360.90, 961.33 +/- A 403.58 and 1,189.75 +/- A 405.80 ng h/mL, respectively; the mean +/- A SD 9-aminocamptothecin C (max) were 12.85 +/- A 6.46, 10.72 +/- A 6.58 and 28.74 +/- A 31.94 ng/mL; AUC(0-36) were 157.61 +/- A 111.61, 88.71 +/- A 39.51 and 173.52 +/- A 122.19 ng h/mL, respectively. In the multiple-dose pharmacokinetic study, the mean +/- A SD 9-nitrocamptothecin AUC(ss) was 907.04 +/- A 736.47 ng h/mL, C (max) was 85.98 +/- A 47.52 ng/mL, C (min) was 18.91 +/- A 22.50 ng/mL, C (av) was 37.79 +/- A 30.69 ng/mL, DF was 2.16 +/- A 0.87; the mean +/- A SD 9-aminocamptothecin AUC(ss) was 442.73 +/- A 308.39 ng h/mL, C (max) was 34.83 +/- A 18.31 ng/mL, C (min) was 10.32 +/- A 6.95 ng/mL, C (av) was 18.45 +/- A 12.85 ng/mL, DF was 1.34 +/- A 0.42. Comparing single-dose 1.5 mg/m(2) group with multiple-dose 1.5 mg/m(2) group, no significant difference was observed in 9-NC pharmacokinetic parameters, but with respect to the metabolite, significant differences were observed in C (max) and AUC. The toxicity of 9-NC varied from mild to moderate. No grade 3 or grade 4 toxicity was observed during the study. There was 2- to 13-fold variabilities in 9-NC and 9-AC exposure among different patients for any given dose of 9-NC. @@@ All participants had good tolerance throughout the study. 9-NC and 9-AC exposure did not increase proportionally to the dose ranging from 1.25 to 1.75 mg/m(2). After 5-day continuous administration, accumulation was observed in the metabolite 9-AC, but not in 9-NC.
