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Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non-small-Cell Lung Cancer Receiving Erlotinib Treatment

Parra-Guillen, Zinnia P. and Berger, Peter B. and Haschke, Manuel and Donzelli, Massimiliano and Winogradova, Daria and Pfister, Bogumila and Früh, Martin and Gillessen, Silke and Krähenbühl, Stephan and Kloft, Charlotte and Joerger, Markus. (2017) Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non-small-Cell Lung Cancer Receiving Erlotinib Treatment. Basic and Clinical Pharmacology and Toxicology, 121 (4). pp. 309-315.

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Official URL: http://edoc.unibas.ch/58936/

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Abstract

Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD was initiated, and the two oral probe drugs midazolam (2 mg) and caffeine (100 mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R2  = 0.960, p < 0.0001), OSI-420 (R2  = 0.971, p < 0.0001), midazolam (R2  = 0.995, p < 0.0001) and caffeine (R2  = 0.968, p < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R2  = 0.33, p = 0.048), while midazolam clearance was not (R2  = -0.09, p = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, p = 0.086 for Student's t-test). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in patients with cancer.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:1742-7835
e-ISSN:1742-7843
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:18 Jun 2018 12:26
Deposited On:18 Jun 2018 12:26

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