title: A phase I pharmacokinetics study of 9-nitrocamptothecin in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  In the single-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin C(max) were 94.49 ± 41.38, 115.56 ± 63.27 and 147.57 ± 38.19 ng/mL; AUC(0-36) were 877.14 ± 360.90, 961.33 ± 403.58 and 1,189.75 ± 405.80 ng h/mL, respectively; the mean ± SD 9-aminocamptothecin C(max) were 12.85 ± 6.46, 10.72 ± 6.58 and 28.74 ± 31.94 ng/mL; AUC(0-36) were 157.61 ± 111.61, 88.71 ± 39.51 and 173.52 ± 122.19 ng h/mL, respectively. In the multiple-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin AUC(ss) was 907.04 ± 736.47 ng h/mL, C(max) was 85.98 ± 47.52 ng/mL, C(min) was 18.91 ± 22.50 ng/mL, C(av) was 37.79 ± 30.69 ng/mL, DF was 2.16 ± 0.87; the mean ± SD 9-aminocamptothecin AUC(ss) was 442.73 ± 308.39 ng h/mL, C(max) was 34.83 ± 18.31 ng/mL, C(min) was 10.32 ± 6.95 ng/mL, C(av) was 18.45 ± 12.85 ng/mL, DF was 1.34 ± 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, 300072 Tianjin, China. yanzhaotj@126.com
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yan
authors.forename: Zhongling
authors.initials: Z
authors.lastname: Zhu
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Liuchun
authors.initials: L
authors.lastname: Wang
authors.forename: Chun
authors.initials: C
authors.lastname: Huang
authors.forename: Jinhuai
authors.initials: J
authors.lastname: Xue
authors.forename: Meijun
authors.initials: M
authors.lastname: Liu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; C079905:rubitecan; D002166:Camptothecin