liu.seSearch for publications in DiVA
Change search
Link to record
Permanent link

Direct link
BETA
Svedberg, Anna
Publications (5 of 5) Show all publications
Svedberg, A. (2020). Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment
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:nbn:se:liu:diva-163123 (URN)10.3384/diss.diva-163123 (DOI)9789179299828 (ISBN)
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
Björn, N., Sigurgeirsson, B., Svedberg, A., Pradhananga, S., Brandén, E., Koyi, H., . . . Gréen, H. (2019). Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia. The Pharmacogenomics Journal
Open this publication in new window or tab >>Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
Show others...
2019 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150Article in journal (Refereed) Epub ahead of print
Abstract [en]

Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

National Category
Cancer and Oncology Medical Genetics Pharmacology and Toxicology Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-162137 (URN)10.1038/s41397-019-0099-8 (DOI)
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2020-01-15Bibliographically approved
Skoglund, K., Richter, J., Olsson-Stromberg, U., Bergquist, J., Aluthgedara, W., Ubhayasekera, S. J., . . . Green, H. (2016). In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia. Therapeutic Drug Monitoring, 38(2), 230-238
Open this publication in new window or tab >>In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia
Show others...
2016 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed) Published
Abstract [en]

Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2016
Keywords
pharmacokinetics; chronic myeloid leukemia; imatinib; CGP74588; CYP3A
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-129678 (URN)10.1097/FTD.0000000000000268 (DOI)000376938000006 ()26693810 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Society; Medical Research Council of Southeast Sweden; Novartis

Available from: 2016-06-27 Created: 2016-06-23 Last updated: 2018-01-10
Vikingsson, S., Strömqvist, M., Svedberg, A., Hansson, J., Höiom, V. & Gréen, H. (2016). Novel rapid liquid chromatography tandem masspectrometry method for vemurafenib and metabolites in human plasma, including metabolite concentrations at steady-state.. BMC Biomedical chromotography, 30(8), 1234-1239
Open this publication in new window or tab >>Novel rapid liquid chromatography tandem masspectrometry method for vemurafenib and metabolites in human plasma, including metabolite concentrations at steady-state.
Show others...
2016 (English)In: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 30, no 8, p. 1234-1239Article in journal (Refereed) Published
Abstract [en]

A novel, rapid and sensitive liquid chromatography tandem-mass spectrometry method for quantification of vemurafenib in human plasma, that also for the first time allows for metabolite semi-quantification, was developed and validated to support clinical trials and therapeutic drug monitoring. Vemurafenib was analysed by precipitation with methanol followed by a 1.9 min isocratic liquid chromatography tandem masspectrometry analysis using an Acquity BEH C18 column with methanol and formic acid using isotope labelled internal standards. Analytes were detected in multi reaction monitoring mode on a Xevo TQ. Semi-quantification of vemurafenib metabolites was performed using the same analytical system and sample preparation with gradient elution. The vemurafenib method was successfully validated in the range 0.5-100 µg/mL according to international guidelines. The metabolite method was partially validated due to the lack of commercially available reference materials. For the first time concentration levels at steady-state for melanoma patients treated with vemurafenib is presented. The low abundance of vemurafenib metabolites suggests that they lack clinical significance. This article is protected by copyright. All rights reserved.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keywords
BRAFV600E; LC-MS/MS; melanoma; metabolites;validation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-126098 (URN)10.1002/bmc.3672 (DOI)000379971200010 ()26683023 (PubMedID)
Note

Funding agencies: Swedish Research Council [C0592901, A0671101]; Swedish Cancer Society [130335]; County Council of Ostergotland; County Council of Stockholm-Gotland; Medical Research Council of Southeast Sweden [388611]; Swedish Medical Research Council; Radiumhemmet Rese

Available from: 2016-03-14 Created: 2016-03-14 Last updated: 2018-03-26Bibliographically approved
Svedberg, A., Green, H., Vikström, A., Lundeberg, J. & Vikingsson, S. (2015). 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. Journal of Pharmaceutical and Biomedical Analysis, 107, 186-195
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
Show others...
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
Organisations

Search in DiVA

Show all publications