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Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment
Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lung cancer is the leading cause of cancer-related deaths worldwide. Unfortunately, lung cancer is usually discovered at a late stage when the curative treatment options are limited. The treatment can include surgery, radiation, chemotherapy, targeted therapy and now also immunotherapy.

The challenge in cancer treatment is to eradicate cancer by the use of harsh treatments, while still, keeping the patient alive. For this purpose, treatments with severe toxicities are usually accepted but regularly lead to dose reductions or postponed treatment. Large variations in response are generally observed between patients treated with the same drug at the same dose. The dose may be adequate in one patient while ineffective or cause severe adverse drug reactions in other patients. The occurrence of drug-induced toxicities can, however, also be a positive indicator of treatment response. In personalized treatment it is of importance to select the most suitable treatment option and give it at the most favorable dose, to enable the patients to stay on treatment during the time the treatment is able to affect cancer since the tumor commonly develops resistance towards the treatment eventually.

In this thesis, inter-individual variability in pharmacokinetics and toxicity for the targeted therapy erlotinib, associated with the adverse events skin rash and diarrhea was studied. Inter-individual variability in toxicity was also studied for the chemotherapy treatment gemcitabine/carboplatin linked to the hematological toxicities neutropenia and leukopenia.

Erlotinib was studied in papers I-IV. Erlotinib and its metabolite concentrations were determined using a validated LC-MS/MS method. Diarrhea was associated with erlotinib and the metabolite M13, while skin rash was associated with the activity of the erlotinib metabolizing enzyme CYP3A and the ABCG2 single nucleotide polymorphism rs10856870. CYP3A was also shown to be induced during treatment. Additionally, in vitro studies showed that genetic variability in ABCG2 contributes to differences in intracellular concentrations. Genes and gene variants were found to be associated with gemcitabine/carboplatininduced toxicity in paper V. The variants were partially validated, and two models were developed to estimate the risk of leukopenia or neutropenia based on a set of genetic variants.

Abstract [sv]

Lungcancer är den cancerform som leder till flest antal dödsfall runt om i världen. Tyvärr upptäcks lungcancer oftast i ett sent skede när möjligheten att bota cancern är begränsad. Lungcancer kan behandlas med flera behandlingsmetoder, antingen enskilt eller i kombination, som till exempel kirurgi, strålning, cellgifter, målriktad behandling eller immunoterapi.

Den stora svårigheten vid cancerbehandling är att eliminera cancern samtidigt som patienten klarar av behandlingen. Cancerbehandling innefattar ofta starka läkemedel som vanligtvis kan ge upphov till svåra biverkningar som resulterar i dosreduktion, uppehåll i behandling eller till och med avslutad behandling. Det finns idag flera behandlingsalternativ att välja mellan. Det är därför av stor vikt att välja en behandlingsmetod som cancertumören svarar på, samtidigt som behandlingen ges i rätt dos för nå önskad effekt. Det finns idag stor variation mellan patienter i hur de svarar på cancerbehandling, vissa patienter får bra effekt av behandlingen medan andra patienter inte får någon effekt alls eller får svåra biverkningar. Tumören har en förmåga att efter en tid utveckla resistens. Det är därför viktigt att patienten behandlas effektivt mot cancern under en så lång period som möjligt när det finns en effekt mot tumören.

I den här avhandlingen har två olika behandlingar vid icke-småcellig lungcancer studerats för att bättre förstå vad som orsakar variation mellan patienter. Den ena behandlingen är en målriktad behandling med erlotinib (Tarceva) som vanligtvis ger biverkningar i form av hudutslag eller diarré. Den andra studerade behandlingen är en kombination av cellgifter, gemcitabin tillsammans med karboplatin, som vanligtvis ger biverkningarna leukopeni och neutropeni som leder till försämrat immunförsvar.

I delarbete I-IV studerades erlotinib, antingen via ett modellsystem i form av en cellinje eller från behandlade lungcancerpatienter. Variation av läkemedelskoncentrationer samt genetisk variation i arvsmassan studerades. Läkemedelskoncentrationer i erlotinibpatienters blod analyserades med en utvecklad och validerad kromatografimetod. Diarré visade sig vara kopplat till koncentrationen av erlotinib och metaboliten M13. Hudbiverkningar var associerade med CYP3A aktivitet, som är enzymet som bryter ner erlotinib i kroppen. CYP3A visade sig också att öka sin aktivitet i samband med att man påbörjar erlotinibbehandling. Hudbiverkningar kopplades också till en kvot av metaboliter (OSI-420/didesmethyl erlotinib) och en naturlig genetisk variation i ABCG2-genen som är involverad i transport av erlotinib ut ur kroppen.

I delarbete V studerades genetisk variation i gemcitabin/carboplatin behandlade lungcancerpatienter. Då identifierades naturlig genetisk variation i arvsmassan kunna förklara en del av variationen i uppkomsten av biverkningar. Flera genetiska varianter användes för att bygga modeller som kan användas för att förutspå om patienter löper hög risk att drabbas av svåra cellgiftsbiverkningar.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. , p. 57
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1708
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-163123DOI: 10.3384/diss.diva-163123ISBN: 9789179299828 (print)OAI: oai:DiVA.org:liu-163123DiVA, id: diva2:1385359
Public defence
2020-02-14, Hasselquistsalen, Linköping University Hospital, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-02-06Bibliographically approved
List of papers
1. A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma
Open this publication in new window or tab >>A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma
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2015 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 107, p. 186-195Article in journal (Refereed) Published
Abstract [en]

A liquid chromatography tandem mass spectrometry method was developed and validated for quantification of erlotinib and its metabolites in human plasma. The method is suitable for therapeutic drug monitoring and pharmacokinetic studies. The substances were extracted using protein precipitation, separated on a BEH XBridge C18 column (100 x 2.1 mm, 1.7 mu m) by gradient elution at 0.7 mL/min of acetonitrile and 5 mM ammonium acetate. The concentration was determined using a Waters Xevo triple quadrupole mass spectrometer in a multi reaction monitoring mode. The total run time was 7 min. Deuterated erlotinib and OSI-597 were used as internal standard for erlotinib and its metabolites, respectively. Erlotinib, OSI-420 and didesmethyl erlotinib were quantified in the concentration range 25-5000 ng/mL, 0.5-500 ng/mL and 0.15-10 ng/mL, respectively. Precision and accuracy was less than14% except for OSI-420 at LLOQ (17%). Extraction recovery was above 89%, 99% and 89% for erlotinib, OSI-420 and didesmethyl erlotinib, respectively. The human liver microsomes generated 14 metabolites, three of them not previously reported. Twelve metabolites were measured semi-quantitatively and validated with respect to selectivity, precision and stability. (C) 2014 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
LC-MS/MS; Human liver microsomes; Non-small cell lung cancer; EGFR; Tyrosine kinase inhibitor
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117227 (URN)10.1016/j.jpba.2014.12.022 (DOI)000351116900024 ()25594896 (PubMedID)
Note

Funding Agencies|Swedish Research Council [C0592901, A0671101]; Swedish Cancer Society [130335]; Medical Research Council of Southeast Sweden [388611]

Available from: 2015-04-23 Created: 2015-04-21 Last updated: 2020-01-14
2. Erlotinib treatment induces cytochrome P450 3A activity in non-small cell lung cancer patients
Open this publication in new window or tab >>Erlotinib treatment induces cytochrome P450 3A activity in non-small cell lung cancer patients
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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, Wilcoxons 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
Keywords
CYP3A activity; erlotinib; non-small cell lung cancer; quinine; Tarceva
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-159123 (URN)10.1111/bcp.13953 (DOI)000475399400007 ()30945322 (PubMedID)
Note

Funding Agencies|Cancerfonden [CAN 2016/602]; Forskningsradet i Sydostra Sverige [760411]; Swedish Research Council; Linkoping University

Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2020-01-14

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