Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies

Autor: Caroline Protin, Fanny Gallais, Ben Allal, Sandra De Barros, Fabienne Thomas, Anne Quillet-Mary, Melanie White-Koning, Etienne Chatelut, Lucie Oberic, Loïc Dupré, Fabien Despas, Loïc Ysebaert
Přispěvatelé: Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Centre de Physiopathologie Toulouse Purpan (CPTP), QUILLET-MARY, Anne, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Adult
Oncology
medicine.medical_specialty
Chronic lymphocytic leukemia
[SDV]Life Sciences [q-bio]
Population
MESH: Adenine / analogs & derivatives
Naphthalenes
030226 pharmacology & pharmacy
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
MESH: Leukemia
Lymphocytic
Chronic
B-Cell* / drug therapy
Piperidines
Pharmacokinetics
Internal medicine
medicine
Humans
Pharmacology (medical)
education
Adverse effect
ComputingMilieux_MISCELLANEOUS
Pharmacology
education.field_of_study
MESH: Humans
MESH: Piperidines / pharmacokinetics
MESH: Adenine / pharmacokinetics
business.industry
Adenine
Area under the curve
MESH: Adult
MESH: Naphthalenes
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
3. Good health
NONMEM
[SDV] Life Sciences [q-bio]
chemistry
030220 oncology & carcinogenesis
Ibrutinib
Mantle cell lymphoma
business
Zdroj: Clinical Pharmacokinetics
Clinical Pharmacokinetics, 2020, 59 (9), pp.1171-1183. ⟨10.1007/s40262-020-00884-0⟩
Clinical Pharmacokinetics, Springer Verlag, 2020, 59 (9), pp.1171-1183. ⟨10.1007/s40262-020-00884-0⟩
ISSN: 0282-4159
0312-5963
1179-1926
DOI: 10.1007/s40262-020-00884-0⟩
Popis: Ibrutinib is used for the treatment of chronic lymphocytic leukemia and other lymphoid malignancies. The aim of this work is to develop a population pharmacokinetic model for ibrutinib and its dihydrodiol metabolite to quantify pharmacokinetic inter- and intra-individual variability, to evaluate the impact of several covariates on ibrutinib pharmacokinetic parameters, and to examine the relationship between exposure and clinical outcome. Patients treated with ibrutinib were included in the study and followed up for 2 years. Pharmacokinetic blood samples were taken from months 1 to 12 after inclusion. Ibrutinib and dihydrodiol-ibrutinib concentrations were assessed using ultra-performance liquid chromatography tandem mass spectrometry. A population pharmacokinetic model was developed using NONMEM version 7.4. A total of 89 patients and 1501 plasma concentrations were included in the pharmacokinetic analysis. The best model consisted in two compartments for each molecule. Absorption was described by a sequential zero first-order process and a lag time. Ibrutinib was either metabolised into dihydrodiol-ibrutinib or excreted through other elimination routes. A link between the dosing compartment and the dihydrodiol-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism. Ibrutinib clearance had 67% and 47% inter- and intra-individual variability, respectively, while dihydrodiol-ibrutinib clearance had 51% and 26% inter- and intra-individual variability, respectively. Observed ibrutinib exposure is significantly higher in patients carrying one copy of the cytochrome P450 3A4*22 variant (1167 ng.h/mL vs 743 ng.h/mL, respectively, p = 0.024). However, no covariates with a clinically relevant effect on ibrutinib or dihydrodiol-ibrutinib exposure were identified in the PK model. An external evaluation of the model was performed. Clinical outcome was expressed as the continuation or discontinuation of ibrutinib therapy 1 year after treatment initiation. Patients who had treatment discontinuation because of toxicity had significantly higher ibrutinib area under the curve (p = 0.047). No association was found between cessation of therapy due to disease progression and ibrutinib area under the curve in patients with chronic lymphocytic leukemia. For the seven patients with mantle cell lymphoma studied, an association trend was observed between disease progression and low exposure to ibrutinib. We present the first population pharmacokinetic model describing ibrutinib and dihydrodiol-ibrutinib concentrations simultaneously. Large inter-individual variability and substantial intra-individual variability were estimated and could not be explained by any covariate. Higher plasma exposure to ibrutinib is associated with cessation of therapy due to the occurrence of adverse events within the first year of treatment. The association between disease progression and ibrutinib exposure in patients with mantle cell lymphoma should be further investigated. ClinicalTrials.gov no. NCT02824159.
Databáze: OpenAIRE
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