title: Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath) in patients with chronic lymphocytic leukaemia and its link to treatment response.
abstract: OBJECTIVE
  To characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL).
  
  
  METHODS
  Nonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response.
  
  
  RESULTS
  Alemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where V(max) (microg h(-1)) was [1020 x (WBC count/10 x 10(9) l(-1))(0.194)], K(m) was 338 microg l(-1), V(1) was 11.3 l, Q was 1.05 l h(-1) and V(2) was 41.5 l. Intersubject variability (ISV) in V(max), K(m), V(1) and V(2) was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for E(max), 306 microg l(-1) for EC(50), 1.56 x 10(9) cells l(-1) h(-1) for K(in) and 0.029 per h for K(out). The probability of achieving a complete or partial response was >/=50% when the maximal trough concentration exceeded 13.2 microg ml(-1) or when AUC(0-tau) exceeded 484 microg h(-1) ml(-1).
  
  
  CONCLUSIONS
  Alemtuzumab displayed time- and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response.
authors.affiliation: Projections Research, Phoenixville, PA, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Mould
authors.forename: A
authors.initials: A
authors.lastname: Baumann
authors.forename: J
authors.initials: J
authors.lastname: Kuhlmann
authors.forename: M J
authors.initials: MJ
authors.lastname: Keating
authors.forename: S
authors.initials: S
authors.lastname: Weitman
authors.forename: P
authors.initials: P
authors.lastname: Hillmen
authors.forename: L R
authors.initials: LR
authors.lastname: Brettman
authors.forename: S
authors.initials: S
authors.lastname: Reif
authors.forename: P L
authors.initials: PL
authors.lastname: Bonate
mesh_terms: D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D007958:Leukocyte Count; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D000074323:Alemtuzumab