Identification of novel pathways of osimertinib disposition and potential implications for the outcome of lung cancer therapy

A. Kenneth MacLeod, De Lin, Jeffrey T.-J. Huang, Lesley A. McLaughlin, Colin J. Henderson, C. Roland Wolf (Lead / Corresponding author)

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Abstract

Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy.

Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolismin vitroA panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathwaysin vivo.

Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized micein vivo.

Conclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model thein vivoeffect of critical metabolic pathways on anti-tumor response.

Original languageEnglish
Pages (from-to)2138-2147
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number9
Early online date6 Feb 2018
DOIs
Publication statusPublished - May 2018

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Lung Neoplasms
Cytochrome P-450 CYP3A
Therapeutics
Pharmaceutical Preparations
Cytochrome P-450 CYP1A2
Lung
Cytochrome P-450 CYP1A1
Enzyme Induction
Critical Pathways
osimertinib
Liver
Cytochromes
Multigene Family
Metabolic Networks and Pathways
Epidermal Growth Factor Receptor
Knockout Mice
Non-Small Cell Lung Carcinoma
Cytochrome P-450 Enzyme System
Neoplasms
Research Design

Cite this

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title = "Identification of novel pathways of osimertinib disposition and potential implications for the outcome of lung cancer therapy",
abstract = "Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy.Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolismin vitroA panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathwaysin vivo.Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized micein vivo.Conclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model thein vivoeffect of critical metabolic pathways on anti-tumor response.",
author = "MacLeod, {A. Kenneth} and De Lin and Huang, {Jeffrey T.-J.} and McLaughlin, {Lesley A.} and Henderson, {Colin J.} and Wolf, {C. Roland}",
note = "This work was supported by Cancer Research UK programme grant C4639/A10822.",
year = "2018",
month = "5",
doi = "10.1158/1078-0432.CCR-17-3555",
language = "English",
volume = "24",
pages = "2138--2147",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
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TY - JOUR

T1 - Identification of novel pathways of osimertinib disposition and potential implications for the outcome of lung cancer therapy

AU - MacLeod, A. Kenneth

AU - Lin, De

AU - Huang, Jeffrey T.-J.

AU - McLaughlin, Lesley A.

AU - Henderson, Colin J.

AU - Wolf, C. Roland

N1 - This work was supported by Cancer Research UK programme grant C4639/A10822.

PY - 2018/5

Y1 - 2018/5

N2 - Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy.Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolismin vitroA panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathwaysin vivo.Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized micein vivo.Conclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model thein vivoeffect of critical metabolic pathways on anti-tumor response.

AB - Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy.Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolismin vitroA panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathwaysin vivo.Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized micein vivo.Conclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model thein vivoeffect of critical metabolic pathways on anti-tumor response.

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U2 - 10.1158/1078-0432.CCR-17-3555

DO - 10.1158/1078-0432.CCR-17-3555

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JO - Clinical Cancer Research

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