PMID- 31561135
OWN - NLM
STAT- MEDLINE
DCOM- 20200608
LR  - 20200608
IS  - 1879-0852 (Electronic)
IS  - 0959-8049 (Linking)
VI  - 121
DP  - 2019 Nov
TI  - Pemetrexed exposure predicts toxicity in advanced non-small-cell lung cancer: A 
      prospective cohort study.
PG  - 64-73
LID - S0959-8049(19)30472-1 [pii]
LID - 10.1016/j.ejca.2019.08.012 [doi]
AB  - 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(1)]) was estimated and related to progression-free survival (PFS)/overall 
      survival (OS). We compared mean AUC(1) (mg.h/L) in patients with and without 
      severe chemotherapy-related adverse events (AEs) during total treatment. Second, 
      different dosing schedules were simulated to minimise the estimated variability 
      (coefficient of variation [CV]) of 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(1) did not predict PFS/OS in treatment-naive 
      patients (n = 95) (OS, hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 
      1.00-1.11; PFS, HR = 1.03, 95% CI: 0.98-1.08). Patients with severe 
      chemotherapy-related AEs (n = 55) had significantly higher AUC(1) values than 
      patients without them (n = 51) (226 +/- 53 vs 190 +/- 31, p < 0.001). Compared with 
      body surface area-based dosing (CV: 22.5%), simulation of estimated glomerular 
      filtration rate (eGFR)-based dosing (CV 18.5%) and fixed dose of 900 mg with 25% 
      dose reduction, if the eGFR<60 mL/min (CV: 19.1%), resulted in less 
      interindividual variability of 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.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Visser, S
AU  - Visser S
AD  - Department of Pulmonary Medicine, Amphia Hospital, Breda, Netherlands; Department 
      of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands; 
      Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
FAU - Koolen, S L W
AU  - Koolen SLW
AD  - Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 
      Netherlands; Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, 
      Netherlands.
FAU - de Bruijn, P
AU  - de Bruijn P
AD  - Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 
      Netherlands.
FAU - Belderbos, H N A
AU  - Belderbos HNA
AD  - Department of Pulmonary Medicine, Amphia Hospital, Breda, Netherlands.
FAU - Cornelissen, R
AU  - Cornelissen R
AD  - Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, 
      Netherlands.
FAU - Mathijssen, R H J
AU  - Mathijssen RHJ
AD  - Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 
      Netherlands.
FAU - Stricker, B H
AU  - Stricker BH
AD  - Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands; 
      Inspectorate of Health Care, Utrecht, Netherlands.
FAU - Aerts, J G J V
AU  - Aerts JGJV
AD  - Department of Pulmonary Medicine, Amphia Hospital, Breda, Netherlands; Department 
      of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands. 
      Electronic address: j.aerts@erasmusmc.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190924
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - 04Q9AIZ7NO (Pemetrexed)
SB  - IM
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*adverse effects
MH  - Carcinoma, Non-Small-Cell Lung/diagnosis/*drug therapy/epidemiology/metabolism
MH  - Cohort Studies
MH  - Disease-Free Survival
MH  - Dose-Response Relationship, Drug
MH  - Drug-Related Side Effects and Adverse Reactions/*diagnosis/epidemiology/etiology
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/diagnosis/*drug therapy/epidemiology/metabolism
MH  - Male
MH  - Middle Aged
MH  - Pemetrexed/*pharmacokinetics/*therapeutic use
MH  - Prognosis
MH  - Prospective Studies
MH  - Survival Analysis
OTO - NOTNLM
OT  - Alternative dosing
OT  - Non-small-cell lung cancer
OT  - PKPD
OT  - Pemetrexed
OT  - Toxicity
EDAT- 2019/09/29 06:00
MHDA- 2020/06/09 06:00
CRDT- 2019/09/28 06:00
PHST- 2019/02/26 00:00 [received]
PHST- 2019/07/21 00:00 [revised]
PHST- 2019/08/05 00:00 [accepted]
PHST- 2019/09/29 06:00 [pubmed]
PHST- 2020/06/09 06:00 [medline]
PHST- 2019/09/28 06:00 [entrez]
AID - S0959-8049(19)30472-1 [pii]
AID - 10.1016/j.ejca.2019.08.012 [doi]
PST - ppublish
SO  - Eur J Cancer. 2019 Nov;121:64-73. doi: 10.1016/j.ejca.2019.08.012. Epub 2019 Sep 
      24.