title: Pharmacokinetics of rituximab in patients with CD20 positive B-cell malignancies.
abstract: BACKGROUND
  In this study, we investigated the pharmacokinetics of rituximab in patients with CD20 positive non-Hodgkin lymphoma, to get more insight into the factors that influence the pharmacokinetics of rituximab. This may aid to understand variability of treatment outcome, in patients with a CD20 positive malignancy treated with rituximab.
  
  
  METHODS
  In this study, patients with a CD20 positive B-cell malignancy who were treated with rituximab containing regimens were included. Induction treatment schedules consisted of a combination of rituximab with chemotherapy for 4-8 cycles. Maintenance treatment consisted of a 2 or 3-monthly dose of 375 mg/m2 rituximab intravenously for 2 years. On the day of the treatment with rituximab, preinfusion blood samples were taken. Also, after the end of treatment, selected blood samples were taken. Rituximab levels were measured with a validated enzyme-linked immunosorbent assay (ELISA). An antigen binding assay was applied for determination of human-antibodies against chimeric-antibodies (HACAs).
  
  
  RESULTS
  Eight patients were on induction therapy. Rituximab levels of one patient on induction therapy remained very low after the first course. This patient had a chronic lymphoid leukemia with circulating tumor cells and a high tumor burden. Apart from one patient with mantle cell lymphoma, all patients on induction therapy had a complete response. Five patients were on maintenance therapy. Trough levels of 4 patients on three-monthly schedule maintenance therapy remained constant, with a median concentration of 6 mu g/mL (range 0.5-11.7 microg/mL). One patient had a relapse during his maintenance treatment. The elimination half-life at steady state of rituximab in all patients was estimated to be 19.2 (+/- 15.2%) days with a between-subject variability of 54%, indicating wide variability. Possible pharmacokinetic-pharmacodynamic relationship was observed as rituximab levels of the non-responders remained low compared to the rituximab levels of the responders. For all patients, concentration of HACAs remained below the quantification limit.
  
  
  CONCLUSIONS
  Considerable inter-individual variability of rituximab levels was observed. Although the patient population was small, the results support the need for more research into the pharmacokinetics and factors that might influence the pharmacokinetic-pharmacodynamic relationships of rituximab in patients with non-Hodgkin lymphoma.
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. Ly.Tran@slz.nl
authors.forename: L
authors.initials: L
authors.lastname: Tran
authors.forename: J W
authors.initials: JW
authors.lastname: Baars
authors.forename: L
authors.initials: L
authors.lastname: Aarden
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002330:Carmustine; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014750:Vincristine; D014751:Vindesine
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine; D014751:Vindesine; D002330:Carmustine; D011241:Prednisone