Pemetrexed exposure predicts toxicity in advanced non-small-cell lung cancer: A prospective cohort study.
Aged
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Carcinoma, Non-Small-Cell Lung
/ diagnosis
Cohort Studies
Disease-Free Survival
Dose-Response Relationship, Drug
Drug-Related Side Effects and Adverse Reactions
/ diagnosis
Female
Humans
Lung Neoplasms
/ diagnosis
Male
Middle Aged
Pemetrexed
/ pharmacokinetics
Prognosis
Prospective Studies
Survival Analysis
Alternative dosing
Non–small-cell lung cancer
PKPD
Pemetrexed
Toxicity
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
26
02
2019
revised:
21
07
2019
accepted:
05
08
2019
pubmed:
29
9
2019
medline:
9
6
2020
entrez:
28
9
2019
Statut:
ppublish
Résumé
We explored whether total exposure to pemetrexed predicts effectiveness and toxicity in advanced non-small-cell lung cancer (NSCLC). Furthermore, we investigated alternative dosing schedules. In this prospective cohort study, patients with advanced NSCLC receiving first- or second-line pemetrexed(/platinum) were enrolled. Plasma sampling was performed weekly (cyclePK) and within 24 h (24hPK) after pemetrexed administration. With population pharmacokinetic/pharmacodynamic modelling, total exposure to pemetrexed during cycle 1 (area under the curve during chemotherapy cycle 1 [AUC For 106 of 165 patients, concentrations of pemetrexed were quantified (24hPK, n = 15; cyclePK, n = 106). After adjusting for prognostic factors, sex, disease stage and World Health Organisation performance score, AUC Higher exposure to pemetrexed does not increase PFS/OS but is significantly associated with increased occurrence of severe toxicity. Our findings suggest that fixed dosing reduces interpatient pharmacokinetic variability and thereby might prevent toxicity, while preserving effectiveness.
Sections du résumé
BACKGROUND
We explored whether total exposure to pemetrexed predicts effectiveness and toxicity in advanced non-small-cell lung cancer (NSCLC). Furthermore, we investigated alternative dosing schedules.
METHODS
In this prospective cohort study, patients with advanced NSCLC receiving first- or second-line pemetrexed(/platinum) were enrolled. Plasma sampling was performed weekly (cyclePK) and within 24 h (24hPK) after pemetrexed administration. With population pharmacokinetic/pharmacodynamic modelling, total exposure to pemetrexed during cycle 1 (area under the curve during chemotherapy cycle 1 [AUC
RESULTS
For 106 of 165 patients, concentrations of pemetrexed were quantified (24hPK, n = 15; cyclePK, n = 106). After adjusting for prognostic factors, sex, disease stage and World Health Organisation performance score, AUC
CONCLUSIONS
Higher exposure to pemetrexed does not increase PFS/OS but is significantly associated with increased occurrence of severe toxicity. Our findings suggest that fixed dosing reduces interpatient pharmacokinetic variability and thereby might prevent toxicity, while preserving effectiveness.
Identifiants
pubmed: 31561135
pii: S0959-8049(19)30472-1
doi: 10.1016/j.ejca.2019.08.012
pii:
doi:
Substances chimiques
Pemetrexed
04Q9AIZ7NO
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
64-73Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.