title: Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma.
abstract: The aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematological toxicity.
  
  
  
  Population PK modelling (using NONMEM) was performed using DOX and DOXol plasma concentration-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematological toxicity was analysed using the Mann-Whitney-Wilcoxon test.
  
  
  
  A five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population estimates for parent drug (CL) and metabolite (CLm) clearance were 62 l h-1and 27 l h-1, respectively. The fraction metabolized to DOXol (Fm) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CLm, the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration-time curve (AUCtotal), the area under the concentration-time curve for DOX (AUC) plus the area under the concentration-time curve for DOXol (AUCm), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was observed, according to an exponential relationship.
  
  
  
  The PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematological toxicity of the parent drug.
authors.affiliation: Department of Pharmaceutical Sciences - Pharmacy and Pharmaceutical Technology, University of Salamanca, Spain.|Salamanca Institute for Biomedical Research (IBSAL), Salamanca, Spain.
authors.forename: Jonás Samuel
authors.initials: JS
authors.lastname: Pérez-Blanco
authors.affiliation: Department of Pharmaceutical Sciences - Pharmacy and Pharmaceutical Technology, University of Salamanca, Spain.|Salamanca Institute for Biomedical Research (IBSAL), Salamanca, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Santos-Buelga
authors.affiliation: Department of Pharmaceutical Sciences - Pharmacy and Pharmaceutical Technology, University of Salamanca, Spain.|Salamanca Institute for Biomedical Research (IBSAL), Salamanca, Spain.
authors.forename: María Del Mar
authors.initials: MD
authors.lastname: Fernández de Gatta
authors.affiliation: Salamanca Institute for Biomedical Research (IBSAL), Salamanca, Spain.|Haematology Department, University Hospital of Salamanca and IBMCC, Cancer Research Centre, Salamanca, Spain.
authors.forename: Jesús María
authors.initials: JM
authors.lastname: Hernández-Rivas
authors.affiliation: Salamanca Institute for Biomedical Research (IBSAL), Salamanca, Spain.|Haematology Department, University Hospital of Salamanca and IBMCC, Cancer Research Centre, Salamanca, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martín
authors.affiliation: Department of Pharmaceutical Sciences - Pharmacy and Pharmaceutical Technology, University of Salamanca, Spain.|Salamanca Institute for Biomedical Research (IBSAL), Salamanca, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: García
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C010013:adriamycinol
keywords: doxorubicin; doxorubicinol; non-Hodgkin's lymphoma; population pharmacokinetics