Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma.

• Abstract: 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. PATIENTS AND 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.
• Authors: Fabienne Thomas, Philippe Rochaix, Melanie White-Koning, Isabelle Hennebelle, Jérôme Sarini, Adil Benlyazid, Laurence Malard, Jean-Louis Lefebvre, Etienne Chatelut, Jean Pierre Delord (Affiliation: EA3035 and Université de Toulouse, Laboratoire de Pharmacologie Clinique et Expérimentale des Médicaments Anticancéreux, 20-24, F-31052 Toulouse, Cedex, France.)
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 45 Issue 13 Pg. 2316-23 (Sep 2009) ISSN: 1879-0852 [Electronic] England
• PMID: 19523815 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCG2 protein, human
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Neoplasm Proteins
• OSI-420
• Quinazolines
• erlotinib

Topics

• ATP-Binding Cassette Transporters (genetics, metabolism)
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (blood, pharmacokinetics)
• Carcinoma, Squamous Cell (blood, drug therapy, genetics)
• Female
• Head and Neck Neoplasms (blood, drug therapy, genetics)
• Humans
• Male
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Proteins (genetics, metabolism)
• Pilot Projects
• Polymorphism, Single Nucleotide (genetics)
• Quinazolines (blood, pharmacokinetics)