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Erlotinib treatment induces cytochrome P450 3A activity in non-small cell lung cancer patients
Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, Clin Pharmacol, SE-58185 Linkoping, Sweden.
Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, Clin Pharmacol, SE-58185 Linkoping, Sweden;Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
Linkoping Univ Hosp, Dept Pulm Med, Linkoping, Sweden.
Kalmar Cty Hosp, Dept Pulm Med, Kalmar, Sweden.
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2019 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, no 8, p. 1704-1709Article in journal (Refereed) Published
Abstract [en]

Aims: Erlotinib is a tyrosine kinase inhibitor used in the treatment of non-small cell lung cancer highly metabolized by the cytochrome P450 (CYP) 3A. Hence, CYP3A4 activity might be a useful predictor of erlotinib pharmacokinetics in personalized medicine. The effect of erlotinib on CYP3A activity was therefore studied in non-small cell lung cancer patients.

Methods: The study included 32 patients scheduled for erlotinib monotherapy. CYP3A activity was assessed using quinine as a probe before and during erlotinib treatment. Plasma from blood samples drawn 16 hours post quinine administration were analysed using HPLC with fluorescence detection to determine the quinine/3-OH-quinine ratio.

Results: Matched samples, available from 13 patients, showed an induction of CYP3A activity (P = 0.003, Wilcoxon's signed rank test) after 2 months of treatment. The quinine/3-OH-quinine ratio decreased from 20.2 (+/- 13.4) at baseline to 11.0 (+/- 4.34). Single-point samples, available from 19 patients, supported the decrease in ratio (P = 0.007, Mann-Whitney U-test). Generally, females had a higher CYP3A activity both at baseline and after two months of treatment. Statistical analysis by gender also showed significant increase in CYP3A activity (males, n = 10, P = 0.001, and females, n = 22, P = 0.001).

Conclusions: An induction of CYP3A activity was observed after 2 months of erlotinib treatment which was also seen when subdividing based on gender. It could be important to take this into consideration for patients co-administering other CYP3A-metabolizing drugs during erlotinib treatment and also makes it difficult to use baseline CYP3A activity to predict erlotinib pharmacokinetics.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 85, no 8, p. 1704-1709
Keywords [en]
CYP3A activity, erlotinib, non-small cell lung cancer, quinine, Tarceva
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-390493DOI: 10.1111/bcp.13953ISI: 000475399400007PubMedID: 30945322OAI: oai:DiVA.org:uu-390493DiVA, id: diva2:1341940
Funder
Swedish Cancer Society, CAN 2016/602Swedish Research CouncilMedical Research Council of Southeast Sweden (FORSS), 760411Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved

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Brandén, EvaKoyi, Hirsh

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