Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath®) in patients with chronic lymphocytic leukaemia and its link to treatment response

D. R. Mould, A. Baumann, J. Kuhlmann, M. J. Keating, S. Weitman, P. Hillmen, L. R. Brettman, S. Reif, P. L. Bonate

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Aims: 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 Vmax (μg h-1) was [1020 × (WBC count/10 × 109 l-1)0.194], Km was 338 μg l-1, V1 was 11.3 l, Q was 1.05 l h-1 and V2 was 41.5 l. Intersubject variability (ISV) in Vmax, Km, V1 and V2 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 μg l-1 for EC50, 1.56 × 109 cells l-1 h-1 for Kin and 0.029 per h for Kout. The probability of achieving a complete or partial response was ≥50% when the maximal trough concentration exceeded 13.2 μg ml-1 or when AUC0-τ exceeded 484 μg 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.

Original languageEnglish (US)
Pages (from-to)278-291
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume64
Issue number3
DOIs
StatePublished - Sep 2007
Externally publishedYes

Keywords

  • Exposure-response
  • Indirect response model
  • Logistic regression
  • Model validation
  • NONMEM
  • Nonlinear pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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