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Cited by 116Chronic Lymphocytic Leukemia ResearchPharmaceutical studies and practicesStatistical Methods in Clinical Trials

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

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Mould, D. R., Baumann, A., Kuhlmann, J., Keating, M. J., Weitman, S., Hillmen, P., Brettman, L. R., Reif, S. +1 more·2007·British Journal of Clinical Pharmacology
DOI 10.1111/j.1365-2125.2007.02914.xPMC PMC2000651
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Abstract

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.

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  • Alemtuzumab, an antibody targeting CD52-expressing tumor cells, showed time-dependent PK with decreased clearance and extended half-life as tumor burden decreases after repeated dosing.

    “For example, alemtuzumab, an antibody targeting CD52‐expressing tumor cells, showed time‐dependent PK with decreased clearance and extended half‐life as tumor burden decreases after repeated dosing.36”

    From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [36]

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Authors
Mould, D. R., Baumann, A., Kuhlmann, J., Keating, M. J., Weitman, S., Hillmen, P., Brettman, L. R., Reif, S., & Bonate, P. L.
Affiliations
  • Bayer (Germany) (DE)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Bonate, P. L.
ORCID
Venue
British Journal of Clinical Pharmacology
Publisher
Wiley
Published
2007-05-16
Volume
64
Issue
3
Pages
278-291
ISSN
  • 0306-5251 (ISSN-L)
  • 1365-2125
DOI
10.1111/j.1365-2125.2007.02914.x
PMC
PMC2000651
OpenAlex
W2100660422
Cited by
116
References
28
Citations by year
2026: 2 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 2 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 9 · 2014: 5 · 2013: 7 · 2012: 8
FWCI
4.72
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • British Journal of Clinical Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Keywords
alemtuzumab, B-cell chronic lymphocytic leukaemia, population pharmacokinetics, pharmacodynamics, exposure-response relationship, white blood cell count, lymphocyte count, nonlinear elimination, two-compartment model, indirect response model, tumor response, interpatient variability, tumor burden, monoclonal antibody therapy
MeSH terms
Alemtuzumab, Adult, Aged, Antibodies, Monoclonal, Antibodies, Neoplasm, Antineoplastic Agents, Dose-Response Relationship, Drug, Female, Humans, Immunoglobulin G, Leukocyte Count, Male, Middle Aged, Models, Biological, Leukemia, Lymphocytic, Chronic, B-Cell, Logistic Models, Nonlinear Dynamics, Antibodies, Monoclonal, Humanized

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