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Br J Clin Pharmacol. 2019 Jun;85(6):1357-1366. doi: 10.1111/bcp.13907. Epub 2019 Apr 13.

Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients.

Author information

1
Laboratory of Pharmacology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
2
CRCT, University of Toulouse, Inserm, Toulouse, France.
3
Laboratory of Rare Human Circulating Cells, University Medical Centre of Montpellier, Montpellier, France.
4
Department of Head Neck Cancer and Laryngology, University Medical Centre of Montpellier, France.
5
Medical Oncology Department, CHU Saint André, Bordeaux, France.
6
Department of Head and Neck Oncology, Gustave Roussy, Villejuif, France.
7
Department of Medical Oncology, Nice, France.
8
Medical Oncology Department, Institute of Cancer of Montpellier, France.
9
Medical Oncology Department, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
10
Department of Head and Neck Surgery, University Hospital Center of Nîmes, France.
11
Department of Radiation Oncology, Clinique Sainte Catherine, Avignon, France.
12
Department of Head and Neck Oncology and Surgery, Hôpital Dupuytren CHU, Limoges, France.
13
Service de Pharmacologie et Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut National de la Recherche Agronomique, Université Paris Saclay, Gif-sur-Yvette, France.
14
Department of Biostatistics, UPRES EA2415, Clinical Research University Institute, Montpellier, France.

Abstract

AIMS:

Cetuximab associated with cisplatin and 5-fluorouracil is used to treat patients with inoperable or metastatic head and neck squamous cell carcinomas (HNSCC) up until disease progression or unacceptable toxicities. To date, no biomarkers of efficacy are available to select patients who will benefit from treatment.

METHODS:

An ancillary pharmacokinetics (PK) exploration was performed in the context of a prospective study investigating circulating-tumour cells vs progression-free survival (PFS). Cetuximab plasma concentrations were analysed according to a population PK model. Individual exposure parameters were confronted with soluble epidermal growth factor receptor (sEGFR) concentrations, tumour response and PFS.

RESULTS:

PK data (28 patients, 203 observations) were best described by a two-compartment model with linear elimination. Performance status (PS) significantly correlated to both cetuximab clearance and central volume of distribution with both parameters increasing by 33.3% (95% CI 1-65.6) for each 1-point increase of PS compared to PS = 0. Univariate analysis showed that patients with higher trough cetuximab concentrations at Day 7 (Cmin,D7 ) had better tumour response (P = 0.03) and longer PFS (P = 0.035). However, multivariate analysis revealed that only PS and tumour size at baseline remained significantly associated with PFS. Levels of sEGFR increased during cetuximab treatment but were not associated with PFS in the multivariate analysis.

CONCLUSIONS:

Our study prospectively indicates that PS is likely a confounding factor in the relationship between cetuximab PK and PFS, patients with a poor PS having lower cetuximab plasma exposure and lower PFS.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02119559.

KEYWORDS:

HNSCC; cetuximab; concentration; efficacy; pharmacokinetics

PMID:
30811063
PMCID:
PMC6533440
[Available on 2020-06-01]
DOI:
10.1111/bcp.13907

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