POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF IRINOTECAN (CPT-11) AND ACTIVE METABOLITE SN-38 DURING PHASE-I TRIALS

Background: Irinotecan (CPT-11) is a novel water-soluble camptothecin derivative selected for clinical testing based on its good in vitro an d in vivo activity in various experimental systems, including pleiotro pic drug-resistant tumors. Its mechanism of action appears mediated th rough topoisomerase I inhibition. The purpose of this study was to des cribe CPT-11 and active metabolite SN-38 population pharmacokinetics, examine patient characteristics that may influence pharmacokinetics, a nd to investigate pharmacokinetic-pharmacodynamic relationships that m ay prove useful in the future clinical management of this drug. Patien ts and methods: As part of 3 Phase I studies including 235 patients, p harmacokinetics of CPT-11 and metabolite SN-38 were determined in 107 patients. CPT-11 was administered as a 30-min i.v. infusion according to 3 different schedules: daily for 3 consecutive days every 3 weeks, weekly for 3 weeks, and once every 3 weeks. Patients characteristics w ere the following: median age 53 years; 62 men, 45 women; 105 caucasia ns, 2 blacks; performance status was 0-1 in 96 patients; tumor sites w ere predominantly colon, rectum, head and neck, lung, ovary and breast ; with the exception of 6 patients, all had been previously treated wi th surgery, chemotherapy and/or radiotherapy. CPT-11 and metabolite SN -38 were simultaneously determined by HPLC using fluorescence detectio n. Pharmacokinetic parameters were determined using model-independent and model-dependent analyses. Results: 168 pharmacokinetic data sets w ere obtained in 107 patients (97 first courses, 43 second courses, 23 third courses, 4 fourth courses, and 1 fifth course). Rebound concentr ations of CPT-11 were frequently observed at about 0.5 to 1 h followin g the end of the i.v. infusion, which is suggestive of enterohepatic r ecycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal hal f-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of d istribution at steady state (Vdss) of 150 L/m(2), and a total body cle arance of 14.3 L/m(2)/h. Model-dependent analysis disclosed a CPT-11 p lasma 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 values to the above modelindependent analysis. The active metabolite SN-38 pr esented rebound concentrations in many courses at about 1 h following the end of the i.v. infusion which is suggestive of enterohepatic recy cling. 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 pos t i.v.). SN-38 plasma decay followed closely that of the parent compou nd 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 d ose). The number of CPT-11 treatments did not influence pharmacokineti c parameters of either the parent compound or metabolite SN-38. Althou gh CPT-11 pharmacokinetics presented an important interpatient variabi lity, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area un der the plasma concentration versus time curves (AUG) increased propor tionally and linearly with dosage (Cmax, r = 0.75, p < 0.001); CPT-I1 AUG, r = 0.88, p < 0.001). An increase in half-life and MRT was observ ed at higher dosages, although this did not influence the linear incre ase 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 t he CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the C PT-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 change in the fraction of drug metabolized into SN-38 (percentage SN-38 AUC/C PT-11 AUC = mean value of 3.08%. There was also no significant influen ce of CPT-11 dose on the 24-h percent recovery of the parent compound or of its metabolite in urine. Patient physio-pathological characteris tics were examined as possible determinant of pharmacokinetics. No det ectable 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 marke rs, e.g., bilirubinemia and gamma-glutamyl transpeptidase. Also of int erest, a significant positive correlation between the metabolic ratio and some liver function parameters were observed, e.g., bilirubinemia, aspartate transferase (AST), and alanine transferase (ALT). For the p harmacokinetic-pharmacodynamic studies, CPT-11 AUC correlated signific antly with the percent de crease of either the white blood cells or th e neutrophils. CPT-11 AUC also correlated significantly with the inten sity of diarrhea, and the intensity of nausea and vomiting. CPT-11 CL correlated negatively with the intensity of the principal toxicities o bserved. Metabolite SN-38 AUC was also significantly correlated with t he percent decrease in white blood cells and neutrophils. Significant correlations were also observed between SN-38 AUC and the intensity of diarrhea, and the intensity of nausea and vomiting. The metabolic rat io did not correlate with any of the principal toxicities encountered in these clinical studies. With regard to antitumor responses, althoug h the optimal schedule and dose were not obviously defined at the begi nning of these phase I trials, 17 tumor responses were nevertheless ob served (2 complete, 9 partial, 6 minor). The observation that most of these responses were obtained at the highest doses administered is hig hly suggestive of a dose-response relationship with this drug. Conclus ions: These data indicate that CPT-11 population pharmacokinetics is l inear within the large dose range investigated, that the number of tre atments do not influence pharmacokinetics, that liver function affects CPT-11 clearance. Also of interest, the intensity of the major toxici ties encountered with this drug (e.g., leukoneutropenia, diarrhea, nau sea and vomiting) correlated with the exposure (AUG) to CPT-11 and met abolite SN-38. A dose-effect relationship was also noted for