Relationship between cytochrome 3A activity, inflammatory status and the risk of docetaxel-induced febrile neutropenia: a prospective study.
BACKGROUND
We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity.


METHODS
Advanced cancer patients with normal liver function, performance status (PS)<3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m2 DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy.


RESULTS
Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P=0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r=0.32; P=0.02).


CONCLUSIONS
Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.
Alexandre
J
J
Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, USA. Electronic address: jalexand@mdanderson.org.
Rey
E
E
Department of Clinical Pharmacology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris.
Girre
V
V
Department of Medical Oncology, Institut Curie, Paris.
Grabar
S
S
Department of Biostatistics, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France.
Tran
A
A
Department of Clinical Pharmacology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris.
Montheil
V
V
Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France.
Rabillon
F
F
Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France.
Dieras
V
V
Department of Medical Oncology, Institut Curie, Paris.
Jullien
V
V
Department of Clinical Pharmacology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris.
Hérait
P
P
Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France.
Pons
G
G
Department of Clinical Pharmacology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris.
Treluyer
J-M
JM
Department of Clinical Pharmacology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris.
Goldwasser
F
F
Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France.
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D000077143:Docetaxel; D005260:Female; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008874:Midazolam / Q000097:blood; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D009503:Neutropenia / Q000139:chemically induced*; D011446:Prospective Studies; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects; D012307:Risk Factors; D043823:Taxoids / Q000009:adverse effects*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D000077143:Docetaxel; D005293:Ferritins; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam