title: Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass.
abstract: Although being used for decades in the treatment of several types of cancer, either alone or in association, only a few data about the pharmacokinetics of doxorubicin (DOX) in humans are available. DOX is frequently used in association with other anticancer drugs in the management of breast cancer. Pharmacokinetic data available in the literature show that after i.v. administration DOX follows a two-compartment open model, with a fast distribution phase followed by a very slow elimination phase. The objective of this work is to perform a pilot study in order to verify if the usual dose adjustment based on body surface area (BSA) would be producing the same plasma concentration-time profiles in patients with normal (<25) and above normal (>25) body mass index (BMI). In order to assess the pharmacokinetics of DOX after a short-term i.v. infusion of 60mg/m(2) of BSA, an experimental design using only five plasma samples of each patient was applied. Samples were collected at 0.00, 0.66 (right after the end of infusion), 1.66, 8.66, and 24.66h. DOX pharmacokinetic profiles were evaluated after quantification of DOX using a new HPLC method developed and validated. Pharmacokinetic parameters (AUC(0-24.66) and C(max)) were analyzed by non-compartmental and compartmental approaches. Significant differences (α=0.05) between overweight and normal weight groups were found with respect to AUC and C(max). After adjustment of dose by weight and by BMI, the compartmental model was used to simulate plasma concentrations and new values for C(max) and AUC(0-24.66) were calculated. The new values obtained using both body weight (BW) and BMI were closer to the normal group than those obtained with BSA. According to the simulation, the differences of AUC and C(max) between the overweight group and the group of patients with normal weight were lower when the dose was adjusted by BW and BMI. These results suggest that more studies must be conducted, with more patients, in order to evaluate the best dose adjustment for DOX in women with breast cancer and overweight.
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil.
authors.forename: Deise Raquel
authors.initials: DR
authors.lastname: Barpe
authors.forename: Daniela Dornelles
authors.initials: DD
authors.lastname: Rosa
authors.forename: Pedro Eduardo
authors.initials: PE
authors.lastname: Froehlich
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D050177:Overweight; D010865:Pilot Projects; D015203:Reproducibility of Results
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin