title: Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia.
abstract: This retrospective analysis characterizes rituximab population pharmacokinetics in combination with fludarabine and cyclophosphamide and its effect on fludarabine and cyclophosphamide disposition in chronic lymphocytic leukemia (CLL) patients. Rituximab concentration data were well described by a 2-compartment model comprising a time-varying clearance component related to the target-mediated clearance pathway and a constant clearance component reflecting catabolic elimination pathway. Marked differences were observed compared to pharmacokinetic parameters for non-Hodgkin lymphoma (NHL) obtained previously: in CLL, time-varying clearance at time zero (CL(2)) was faster, volumes of distribution (V(1) and V(2)) were larger, and rate of change (K(des)) from the targetmediated clearance pathway to catabolic elimination was lower than NHL. Fludarabine and cyclophosphamide disposition showed no apparent change when co-administered with rituximab. A positive correlation between pharmacokinetic parameters and clinical response was observed, supporting the use of the higher rituximab dose of 500 mg/m(2) in CLL patients (vs 375 mg/m(2) in NHL) to achieve an effective clinical response.
authors.affiliation: Clinical Pharmacology, MS 463a, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA. li.jing@gene.com
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhi
authors.forename: Michael
authors.initials: M
authors.lastname: Wenger
authors.forename: Nancy
authors.initials: N
authors.lastname: Valente
authors.forename: Anna
authors.initials: A
authors.lastname: Dmoszynska
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.forename: Ranvir
authors.initials: R
authors.lastname: Mangat
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Visich
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D003520:Cyclophosphamide / Q000008:administration & dosage; D004347:Drug Interactions; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012189:Retrospective Studies; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine