Population Pharmacokinetics and Pharmacodynamics of Carfilzomib in Combination with Rituximab, Ifosfamide, Carboplatin, and Etoposide in Adult Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.
Adult
Humans
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Carboplatin
/ therapeutic use
Etoposide
/ pharmacology
Ifosfamide
/ pharmacology
Leukocytes, Mononuclear
/ pathology
Lymphoma, Large B-Cell, Diffuse
/ drug therapy
Lymphoma, Non-Hodgkin
/ drug therapy
Neoplasm Recurrence, Local
/ drug therapy
Prospective Studies
Proteasome Endopeptidase Complex
/ therapeutic use
Rituximab
/ pharmacology
Journal
Targeted oncology
ISSN: 1776-260X
Titre abrégé: Target Oncol
Pays: France
ID NLM: 101270595
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
accepted:
12
08
2023
medline:
25
9
2023
pubmed:
27
8
2023
entrez:
26
8
2023
Statut:
ppublish
Résumé
In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL. This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients. In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified. A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE. ClinicalTrials.gov identifier number NCT01959698.
Sections du résumé
BACKGROUND
In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL.
OBJECTIVE
This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients.
PATIENTS AND METHODS
In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m
RESULTS
Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified.
CONCLUSIONS
A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov identifier number NCT01959698.
Identifiants
pubmed: 37632592
doi: 10.1007/s11523-023-00992-4
pii: 10.1007/s11523-023-00992-4
doi:
Substances chimiques
Carboplatin
BG3F62OND5
carfilzomib
72X6E3J5AR
Etoposide
6PLQ3CP4P3
Ifosfamide
UM20QQM95Y
Proteasome Endopeptidase Complex
EC 3.4.25.1
Rituximab
4F4X42SYQ6
Banques de données
ClinicalTrials.gov
['NCT01959698']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
685-695Subventions
Organisme : NCI NIH HHS
ID : P30 CA016056
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA016056
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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