RESUMO
In this study we propose for the first time a limited sampling strategy to estimate the individual pharmacokinetic parameters of both irinotecan and SN-38 in patients treated with the irinotecan plus 5-fluorouracil (FOLFIRI) regimen. The pharmacokinetics of irinotecan and SN-38 were studied in 74 patients with advanced inoperable digestive cancer. Plasma concentrations were taken during and up to the 42 h following a 90-min infusion of irinotecan (180-225 mg/m(2)). Data splitting was used to create model-building and validation data sets, and data were analysed with the NONMEM program. The disposition of SN-38 was dependent on the disposition of irinotecan. The estimated pharmacokinetic parameters of irinotecan [terminal half-life (t(1/2)), 11.5 h; total clearance (CL), 25.0 l h(-1); area under curve (AUC), 14.9 mg x h l(-1)] and SN-38 (terminal t(1/2), 32.2 h; AUC, 0.42 mg x h l(-1)) were similar to those determined in other studies. The protocol involving two sampling times, at 1 and 24 h following the beginning of the infusion, allowed for a precise and accurate determination of the individual pharmacokinetic parameters of the two drugs. The limited sampling strategy developed in this study ought to facilitate future studies on the pharmacology and toxicity of irinotecan-based therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Superfície Corporal , Peso Corporal , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Metástase Neoplásica , Reprodutibilidade dos TestesRESUMO
PURPOSE: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic-pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. METHODS: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m(2); 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. RESULTS: The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m(2) and 211 l/m(2), respectively. The intrapatient variability (22-28%) was far lower than the interindividual variability (33-88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. CONCLUSIONS: All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant.