Population pharmacokinetics of lenalidomide in patients with B‐cell malignancies

Aims Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose‐related toxicities including tumour flare and tumour lysis syndrome. This study aimed to...

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Bibliographic Details
Published in:British journal of clinical pharmacology 2019-05, Vol.85 (5), p.924-934
Main Authors: Hughes, Jim H., Phelps, Mitch A., Upton, Richard N., Reuter, Stephanie E., Gao, Yue, Byrd, John C., Grever, Michael R., Hofmeister, Craig C., Marcucci, Guido, Blum, William, Blum, Kristie A., Foster, David J.R.
Format: Article
Language:English
Subjects:
absorption
Administration, Oral
Adult
Aged
B-Lymphocytes - immunology
Biological Availability
chemotherapy
Clinical Trials, Phase I as Topic
Creatinine - blood
Creatinine - metabolism
Creatinine - urine
Datasets as Topic
Dose-Response Relationship, Drug
Female
Humans
Immunologic Factors - administration & dosage
Immunologic Factors - adverse effects
Immunologic Factors - pharmacokinetics
Lenalidomide - administration & dosage
Lenalidomide - adverse effects
Lenalidomide - pharmacokinetics
Leukemia, Lymphocytic, Chronic, B-Cell - blood
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell - immunology
Leukemia, Myeloid, Acute - blood
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - immunology
Male
Middle Aged
Models, Biological
Multiple Myeloma - blood
Multiple Myeloma - drug therapy
Multiple Myeloma - immunology
NONMEM
Original
pharmacometrics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology
P‐glycoprotein
Renal Elimination
Young Adult
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Summary:Aims Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose‐related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease‐related differences in disposition. Methods Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5–75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. Results The data were best fitted by a 1‐compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat‐free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8–13.6), 68.8 L (61.8–76.3), and 13.5 h−1 (11.9–36.8) respectively. Patients with impaired renal function (creatinine clearance
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.13873