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Titolo:
POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF IRINOTECAN (CPT-11) AND ACTIVE METABOLITE SN-38 DURING PHASE-I TRIALS
Autore:
CHABOT GG; ABIGERGES D; CATIMEL G; CULINE S; DEFORNI R; EXTRA JM; MAHJOUBI H; HERAIT P; ARMAND JP; BUGAT R; CLAVEL M; MARTY ME;
Indirizzi:
INST GUSTAVE ROUSSY,CLIN PHARMACOL LAB,CNRS,URA 147,PAVILLON RECH 2 F-94805 VILLEJUIF FRANCE INST GUSTAVE ROUSSY,DEPT ADULT MED VILLEJUIF FRANCE CTR LEON BERARD F-69373 LYON FRANCE HOP ST LOUIS PARIS FRANCE CTR CLAUDIUS REGAUD TOULOUSE FRANCE LAB BELLON NEUILLY FRANCE
Titolo Testata:
Annals of oncology
fascicolo: 2, volume: 6, anno: 1995,
pagine: 141 - 151
SICI:
0923-7534(1995)6:2<141:PPAPOI>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELL LUNG-CANCER; CAMPTOTHECIN ANALOG CPT-11; DNA TOPOISOMERASE-I; ANTITUMOR-ACTIVITY; MURINE TUMORS; NSC-100880; LEUKEMIA; DRUG; RESISTANCE; MECHANISM;
Keywords:
CAMPTOTHECIN ANALOG; CPT-11; IRINOTECAN; METABOLITE SN-38; POPULATION PHARMACOKINETICS; PHARMACODYNAMICS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
54
Recensione:
Indirizzi per estratti:
Citazione:
G.G. Chabot et al., "POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF IRINOTECAN (CPT-11) AND ACTIVE METABOLITE SN-38 DURING PHASE-I TRIALS", Annals of oncology, 6(2), 1995, pp. 141-151

Abstract

Background: Irinotecan (CPT-11) is a novel water-soluble camptothecinderivative selected for clinical testing based on its good in vitro and in vivo activity in various experimental systems, including pleiotropic drug-resistant tumors. Its mechanism of action appears mediated through topoisomerase I inhibition. The purpose of this study was to describe CPT-11 and active metabolite SN-38 population pharmacokinetics,examine patient characteristics that may influence pharmacokinetics, and to investigate pharmacokinetic-pharmacodynamic relationships that may prove useful in the future clinical management of this drug. Patients and methods: As part of 3 Phase I studies including 235 patients, pharmacokinetics of CPT-11 and metabolite SN-38 were determined in 107patients. CPT-11 was administered as a 30-min i.v. infusion accordingto 3 different schedules: daily for 3 consecutive days every 3 weeks,weekly for 3 weeks, and once every 3 weeks. Patients characteristics were the following: median age 53 years; 62 men, 45 women; 105 caucasians, 2 blacks; performance status was 0-1 in 96 patients; tumor sites were predominantly colon, rectum, head and neck, lung, ovary and breast; with the exception of 6 patients, all had been previously treated with surgery, chemotherapy and/or radiotherapy. CPT-11 and metabolite SN-38 were simultaneously determined by HPLC using fluorescence detection. Pharmacokinetic parameters were determined using model-independentand model-dependent analyses. Results: 168 pharmacokinetic data sets were obtained in 107 patients (97 first courses, 43 second courses, 23third courses, 4 fourth courses, and 1 fifth course). Rebound concentrations of CPT-11 were frequently observed at about 0.5 to 1 h following the end of the i.v. infusion, which is suggestive of enterohepatic recycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal half-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of distribution at steady state (Vdss) of 150 L/m(2), and a total body clearance of 14.3 L/m(2)/h. Model-dependent analysis disclosed a CPT-11 plasma disposition as either biphasic or triphasic with a mean terminal half-life of 12.0 h. The volume of distribution Vdss (150 L/m(2)) and total body clearance (14.8 L/m(2)/h) yielded almost identical valuesto the above modelindependent analysis. The active metabolite SN-38 presented rebound concentrations in many courses at about 1 h followingthe end of the i.v. infusion which is suggestive of enterohepatic recycling. The mean time at which SN-38 maximum concentrations was reached was at 1 h since the beginning of the 0.5 h infusion (i.e., 0.5 h post i.v.). SN-38 plasma decay followed closely that of the parent compound with a mean apparent terminal half-life of 10.6 h. Mean 24 h CPT-11 urinary excretion represented 16.7% of the administered dose, whereas metabolite SN-38 recovery in urine was minimal (0.23% of the CPT-II dose). The number of CPT-11 treatments did not influence pharmacokinetic parameters of either the parent compound or metabolite SN-38. Although CPT-11 pharmacokinetics presented an important interpatient variability, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area under the plasma concentration versus time curves (AUG) increased proportionally and linearly with dosage (Cmax, r = 0.75, p < 0.001); CPT-I1AUG, r = 0.88, p < 0.001). An increase in half-life and MRT was observed at higher dosages, although this did not influence the linear increase in AUC as a function of dose. The volume of distribution at steady state (Vdss) and the total body clearance (CL) were not affected by the CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the CPT-11 dose (r = 0.67, p < 0.001) and also with the parent compound AUC (r = 0.75, p < 0.001). The increase in dose did not lead to a changein the fraction of drug metabolized into SN-38 (percentage SN-38 AUC/CPT-11 AUC = mean value of 3.08%. There was also no significant influence of CPT-11 dose on the 24-h percent recovery of the parent compoundor of its metabolite in urine. Patient physio-pathological characteristics were examined as possible determinant of pharmacokinetics. No detectable relationship was observed between CL or the metabolic ratio (% SN-38 AUC/CPT-11 AUG), with the following physiopathological factors: age, sex, height, weight, body surface, tumor type, or renal function. However, with regard to hepatic function, significant correlations (negative) were observed with CPT-11 CL and some hepatic function markers, e.g., bilirubinemia and gamma-glutamyl transpeptidase. Also of interest, a significant positive correlation between the metabolic ratioand some liver function parameters were observed, e.g., bilirubinemia, aspartate transferase (AST), and alanine transferase (ALT). For the pharmacokinetic-pharmacodynamic studies, CPT-11 AUC correlated significantly with the percent de crease of either the white blood cells or the neutrophils. CPT-11 AUC also correlated significantly with the intensity of diarrhea, and the intensity of nausea and vomiting. CPT-11 CLcorrelated negatively with the intensity of the principal toxicities observed. Metabolite SN-38 AUC was also significantly correlated with the percent decrease in white blood cells and neutrophils. Significantcorrelations were also observed between SN-38 AUC and the intensity of diarrhea, and the intensity of nausea and vomiting. The metabolic ratio did not correlate with any of the principal toxicities encounteredin these clinical studies. With regard to antitumor responses, although the optimal schedule and dose were not obviously defined at the beginning of these phase I trials, 17 tumor responses were nevertheless observed (2 complete, 9 partial, 6 minor). The observation that most ofthese responses were obtained at the highest doses administered is highly suggestive of a dose-response relationship with this drug. Conclusions: These data indicate that CPT-11 population pharmacokinetics is linear within the large dose range investigated, that the number of treatments do not influence pharmacokinetics, that liver function affects CPT-11 clearance. Also of interest, the intensity of the major toxicities encountered with this drug (e.g., leukoneutropenia, diarrhea, nausea and vomiting) correlated with the exposure (AUG) to CPT-11 and metabolite SN-38. A dose-effect relationship was also noted for

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Documento generato il 05/12/20 alle ore 00:43:14