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Titolo:
PHASE-I AND PHARMACOLOGY STUDY OF INTOPLICINE (RP-60475 NSC-645008), A NOVEL TOPOISOMERASE-I AND TOPOISOMERASE-II INHIBITOR, IN CANCER-PATIENTS
Autore:
ABIGERGES D; ARMAND JP; CHABOT GG; BRUNO R; BISSERY MC; BAYSSAS M; KLINKALAKL M; CLAVEL M; CATIMEL G;
Indirizzi:
INST GUSTAVE ROUSSY,DEPT MED,39 RUE CAMILLE DESMOULINS F-94805 VILLEJUIF FRANCE INST GUSTAVE ROUSSY,DEPT MED F-94805 VILLEJUIF FRANCE INST GUSTAVE ROUSSY,DEPT PHARMACOL,CNRS,URA 147 F-94805 VILLEJUIF FRANCE CTR RECH VITRY ALFORTVILLE VITRY FRANCE RHONE POULENC RORER SA ANTONY FRANCE CTR LEON BERARD F-69373 LYON FRANCE
Titolo Testata:
Anti-cancer drugs
fascicolo: 2, volume: 7, anno: 1996,
pagine: 166 - 174
SICI:
0959-4973(1996)7:2<166:PAPSOI>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
BREAKAGE-REUNION REACTION; ANTITUMOR DRUG; DNA; CAMPTOTHECIN; DERIVATIVES; CPT-11; AGENTS;
Keywords:
INTOPLICINE; NSC 645008; PHARMACOKINETICS; PHASE I; RP 60475;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
23
Recensione:
Indirizzi per estratti:
Citazione:
D. Abigerges et al., "PHASE-I AND PHARMACOLOGY STUDY OF INTOPLICINE (RP-60475 NSC-645008), A NOVEL TOPOISOMERASE-I AND TOPOISOMERASE-II INHIBITOR, IN CANCER-PATIENTS", Anti-cancer drugs, 7(2), 1996, pp. 166-174

Abstract

Intoplicine (RP 60475F3 NSC 645008) is a novel 7H-benzo[e]pyrido[4,3-b]indole derivative which interacts with both topoisomerases I and II. Because of its high activity in preclinical cancer models, original mechanism of action and acceptable toxicity profile, intoplicine was further evaluated in a phase I and pharmacology study. Thirty-three (33)patients (24 men and nine women) meeting standard phase I eligibilitycriteria were included: median age was 56 years, performance status 0-1 in 28 patients and 2 in five patients. Tumor primary sites were head and neck (9), colon (6), lung (3) and various other sites (15). Thirty-one patients had received prior radiotherapy and/or chemotherapy. Sixty-nine courses of intoplicine were administered as a 1 h i.v. infusion at dose levels ranging from 12 to 360 mg/m(2). Dose-dependent and reproducible hepatotoxicity was dose limiting in three out of four patients at 360 mg/m(2): this toxicity was reversible in two of three patients, but was fatal in one. Two sudden deaths occurred in this study at 12 and 48 mg/m(2), and the drug implication could not be excluded. No myelosuppression was noted. Hepatotoxicity is therefore dose limiting at 360 mg/m(2), and the phase II recommended dose is 270 mg/m(2) every 3 weeks with close monitoring of hepatic and cardiac functions. Intoplicine pharmacokinetics was determined in plasma (23 patients) and whole blood (18 patients) at doses ranging from 12 to 360 mg/m(2). Intoplicine plasma concentration decay was either bi- or triphasic with the following pharmacokinetic values (mean +/- SEM): half-life alpha, 0.04 +/- 0.004 h; half-life beta, 0.61 +/- 0.13 h; terminal half-life, 19.4 +/- 4.0 h; mean residence time (MRT), 11.3+/-2.4 h; total plasma clearance (CL), 74 +/- 5 l/h; volume of distribution beta (V-beta), 1982 +/- 477 l; volume of distribution at steady state (V-ss): 802 +/- 188 l. Both the area under the plasma concentration versus time curves (AUG) and the maximum plasma concentrations (C-max) increased linearlywith the intoplicine dose, indicating linear pharmacokinetics (AUG: r= 0.937; slope = 0.01305; p < 0.001; C-max: r = 0.847; slope = 0.01115; p < 0.001). Plasma AUC was also predicted very accurately by the C-max values (r = 0.909; slope = 1.0701; p < 0.001). Other plasma pharmacokinetic parameter values increased significantly with dose, e.g. theterminal half-life (r = 0.748, p < 0.001) the MRT (r = 0.728, p < 0.001), the V-beta (r = 0.809, p < 0.001), and the V-ss (r = 0.804, p < 0.001). This was probably due to a longer detectability of the drug in plasma at higher doses. Blood pharmacokinetics was also evaluated in 18 patients since it was found that red blood cells represented a significant drug reservoir for intoplicine. Blood intoplicine disposition curves were either bi- or triphasic with the following pharmacokinetic parameter values (mean +/- SEM): half-life alpha, 0.04 +/- 0.01 h; half-life beta, 0.94 +/- 0.22 h; terminal half-life, 57.1 +/- 6.6 h; MRT,82.2 +/- 9.9 h; CL, 18 +/- 3 l/h; V-beta, 1188 +/- 147 l; V-ss 1163 +/- 138 l. Blood pharmacokinetics was linear, since AUC and C-max increased linearly with dose (AUC: r = 0.879; slope = 0.06884; p < 0.001; C-max r = 0.835, slope = 0.01223; p < 0.001). Blood AUC values could also be determined by the blood C-max (r = 0.768; slope = 5.0206; p < 0.001). Other blood pharmacokinetic parameter values presented a dose dependence, e.g. the terminal half-life (r = 0.626, p = 0.005), the V-beta (r = 0.682, p = 0.002) and the V-ss (r = 0.555, p = 017). The plasma or blood intoplicine concentrations achieved in vivo in humans are potentially cytotoxic levels based on preclinical in vivo and in vitro data. In conclusion, the phase II recommended dose of intoplicine is 270 mg/m(2) administered as a 1 h i.v. infusion every 3 weeks. Plasma and blood pharmacokinetics were linear within the dose range studied. Potentially cytotoxic concentrations were reached at clinically achievable doses.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 01:35:25