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Population pharmacokinetics–pharmacodynamics of alemtuzumab (Campath ® ) in patients with chronic lymphocytic leukaemia and its link to treatment response
Author(s) -
Mould D. R.,
Baumann A.,
Kuhlmann J.,
Keating M. J.,
Weitman S.,
Hillmen P.,
Brettman L. R.,
Reif S.,
Bonate P. L.
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02914.x
Subject(s) - pharmacokinetics , alemtuzumab , pharmacodynamics , medicine , nonmem , population , white blood cell , chronic lymphocytic leukemia , gastroenterology , pharmacology , leukemia , environmental health , transplantation
What is already known about this subject • The pharmacokinetics of alemtuzumab have been incompletely described to date. • At most, presentations of half‐life have been reported in clinical articles using data at the individual level. What this paper adds • This paper presents a comprehensive population pharmacokinetic–pharmacodynamic model for alemtuzumab in B‐CLL patients using lymphocyte counts as the biomarker and links the model to clinical outcomes. 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 V max (µg h −1 ) was [1020 × (WBC count/10 × 10 9 l −1 ) 0.194 ], K m was 338 µg 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 µg l −1 for EC 50 , 1.56 × 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 µg ml −1 or when AUC 0–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.