title: Population pharmacokinetics of rituximab in patients with diffuse large B-cell lymphoma and association with clinical outcome.
abstract: Pharmacokinetic (PK) studies suggest that there is a room for improvement in clinical use of rituximab through more individualized treatment. The objective of this study was to characterize rituximab PK in 29 newly diagnosed patients with diffuse large B-cell lymphoma treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and methylprednisolone every 3 weeks. We also evaluated the association of rituximab PK with clinical outcome.
  
  
  
  Rituximab serum levels were determined by enzyme-linked immunosorbent assay and evaluated by a population PK analysis applying nonlinear mixed effects modelling.
  
  
  
  The data were best described by a two-compartment model comprising linear nonspecific clearance of 0.252 [95% confidence interval (CI): 0.227-0.279] l day-1and time-varying specific clearance of 0.278 (95% CI: 0.181-0.390) l day-1, corresponding to target-mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Additionally, volume of the central compartment was higher in males. A clear association of clinical response with rituximab PK has been observed. Rate constant of specific clearance decay was 0.143 day-1(95% CI: 0.0478-0.418) in patients with no disease progression, while in patients with disease progression it was 82.2% lower (95% CI: 33.4-95.0).
  
  
  
  This finding indicates that time-changes in clearance could serve as a predictive marker of response to rituximab. Our report demonstrates the rationale for studies evaluating higher doses of rituximab in selected patients.
authors.affiliation: Pharmacy Department, Institute of Oncology, Ljubljana, Slovenia and Faculty of Pharmacy, University of Ljubljana, Slovenia.|Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Slovenia.
authors.forename: Samo
authors.initials: S
authors.lastname: Rozman
authors.affiliation: Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Slovenia.
authors.forename: Iztok
authors.initials: I
authors.lastname: Grabnar
authors.affiliation: Department of Molecular Diagnostics, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Novaković
authors.affiliation: Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Slovenia.
authors.forename: Ales
authors.initials: A
authors.lastname: Mrhar
authors.affiliation: Department of Malignant Lymphomas, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jezeršek Novaković
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000401:mortality*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011446:Prospective Studies; D000069283:Rituximab / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012737:Sex Factors; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab
keywords: clinical outcome; diffuse large B-cell lymphoma; pharmacokinetics; rituximab