PHASE-I AND PHARMACOLOGY STUDY OF INTOPLICINE (RP-60475 NSC-645008), A NOVEL TOPOISOMERASE-I AND TOPOISOMERASE-II INHIBITOR, IN CANCER-PATIENTS

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 me chanism of action and acceptable toxicity profile, intoplicine was fur ther evaluated in a phase I and pharmacology study. Thirty-three (33) patients (24 men and nine women) meeting standard phase I eligibility criteria 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). Thirt y-one patients had received prior radiotherapy and/or chemotherapy. Si xty-nine courses of intoplicine were administered as a 1 h i.v. infusi on at dose levels ranging from 12 to 360 mg/m(2). Dose-dependent and r eproducible hepatotoxicity was dose limiting in three out of four pati ents at 360 mg/m(2): this toxicity was reversible in two of three pati ents, but was fatal in one. Two sudden deaths occurred in this study a t 12 and 48 mg/m(2), and the drug implication could not be excluded. N o myelosuppression was noted. Hepatotoxicity is therefore dose limitin g at 360 mg/m(2), and the phase II recommended dose is 270 mg/m(2) eve ry 3 weeks with close monitoring of hepatic and cardiac functions. Int oplicine pharmacokinetics was determined in plasma (23 patients) and w hole blood (18 patients) at doses ranging from 12 to 360 mg/m(2). Into plicine plasma concentration decay was either bi- or triphasic with th e following pharmacokinetic values (mean +/- SEM): half-life alpha, 0. 04 +/- 0.004 h; half-life beta, 0.61 +/- 0.13 h; terminal half-life, 1 9.4 +/- 4.0 h; mean residence time (MRT), 11.3+/-2.4 h; total plasma c learance (CL), 74 +/- 5 l/h; volume of distribution beta (V-beta), 198 2 +/- 477 l; volume of distribution at steady state (V-ss): 802 +/- 18 8 l. Both the area under the plasma concentration versus time curves ( AUG) and the maximum plasma concentrations (C-max) increased linearly with 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-m ax values (r = 0.909; slope = 1.0701; p < 0.001). Other plasma pharmac okinetic parameter values increased significantly with dose, e.g. the terminal half-life (r = 0.748, p < 0.001) the MRT (r = 0.728, p < 0.00 1), 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 p lasma at higher doses. Blood pharmacokinetics was also evaluated in 18 patients since it was found that red blood cells represented a signif icant drug reservoir for intoplicine. Blood intoplicine disposition cu rves were either bi- or triphasic with the following pharmacokinetic p arameter 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 increa sed 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 als o be determined by the blood C-max (r = 0.768; slope = 5.0206; p < 0.0 01). Other blood pharmacokinetic parameter values presented a dose dep endence, e.g. the terminal half-life (r = 0.626, p = 0.005), the V-bet a (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 po tentially cytotoxic levels based on preclinical in vivo and in vitro d ata. In conclusion, the phase II recommended dose of intoplicine is 27 0 mg/m(2) administered as a 1 h i.v. infusion every 3 weeks. Plasma an d blood pharmacokinetics were linear within the dose range studied. Po tentially cytotoxic concentrations were reached at clinically achievab le doses.