Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma.
A clinical study was conducted to determine the safety and efficacy of neoadjuvant erlotinib treatment in patients with head and neck squamous cell carcinoma [Thomas F, Rochaix P, Benlyazid A, et al. Pilot study of neoadjuvant treatment with erlotinib in non-metastatic head and neck squamous cell carcinoma. Clin Cancer Res 2007;13:7086-92]. The aim of the present analysis was to explore the impact of several covariates on the pharmacokinetics of erlotinib and its main metabolite (OSI-420) and to determine PK/PD relationships.


METHODS
Plasma concentrations of erlotinib and OSI-420 of 42 patients were analysed using the NONMEM program to evaluate the impact of patients' covariates on erlotinib pharmacokinetics. The presence of single nucleotide polymorphisms (SNP) in ABCB1 (2677G>T/A and 3435C>T), ABCG2 (421C>A) and CYP3A5 (6986G>A) was investigated. Pharmacokinetic/pharmacodynamic relationships between plasma drug exposure (AUC) and early drug response or toxicity were also studied.


RESULTS
The covariates retained to predict erlotinib clearance were ALAT (alanine amino transferase), age and ABCG2 polymorphism. A significant link between drug exposure and the grade of skin rash was observed but early response to treatment was not correlated to the erlotinib AUC.


CONCLUSIONS
Erlotinib treatment may present criteria justifying dose individualisation but further studies, including more patients, are necessary to define the modalities of this adaptation.
Thomas
Fabienne
F
EA3035 and Université de Toulouse, Laboratoire de Pharmacologie Clinique et Expérimentale des Médicaments Anticancéreux, 20-24, F-31052 Toulouse, Cedex, France.
Rochaix
Philippe
P
White-Koning
Melanie
M
Hennebelle
Isabelle
I
Sarini
Jérôme
J
Benlyazid
Adil
A
Malard
Laurence
L
Lefebvre
Jean-Louis
JL
Chatelut
Etienne
E
Delord
Jean Pierre
JP
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D002294:Carcinoma, Squamous Cell / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; C487471:OSI-420; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride