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 language | English (US) |
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Pages (from-to) | 278-291 |
Number of pages | 14 |
Journal | British Journal of Clinical Pharmacology |
Volume | 64 |
Issue number | 3 |
DOIs | |
State | Published - Sep 2007 |
Externally published | Yes |
Keywords
- Exposure-response
- Indirect response model
- Logistic regression
- Model validation
- NONMEM
- Nonlinear pharmacokinetics
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)